Lynch syndrome–associated urothelial carcinoma: clinical and molecular findings from a single-institution cohort - A. Rametta; M. Barella; A. Scardino; F. Barbetta; E. Tamborini; F. Perrone; A. Busico; L. Agnelli; S. Rota; E. Gusmaroli; M. Stellato; A. Nuzzo; et al. (Familial Cancer, 2026)

The evolution of hereditary cancer genetic counselling: mainstreaming, service redesign and patient experience in Lynch syndrome - Kelly Kohut; Sarah Cable; Alekhya Ashokan; Stefania Vicari; Hannah Ditchfield; Julie Young; Ben Bux; Fiona Lalloo (Familial Cancer, 2026)
Genetic counselling for hereditary cancer predisposition has evolved substantially over more than three decades, driven by advances in genomic technologies and the growing use of tumour and germline testing. These developments have expanded access to hereditary cancer testing, treatment and prevention, while also introducing new clinical, psychosocial and system-level challenges. This review examines the transition from traditional specialist-led genetic counselling to mainstreamed testing pathways. Using Lynch syndrome as a paradigm, we explore how service redesign, personalised risk communication and patient experience intersect in contemporary hereditary cancer care. This invited review synthesises clinical, academic and patient perspectives on the evolution of hereditary cancer genetic counselling. Lived experiences of Lynch syndrome were incorporated through patient and public involvement contributors involved in manuscript development and interpretation. Mainstreamed testing has expanded access to genomic information and strengthened opportunities for cascade testing and prevention within families. However, it has also increased testing volumes, complexity of results interpretation and reliance on non-genetics clinicians. As a result, effective care requires close coordination between genetics and cancer services, alongside support for shared decision-making, family communication and psychosocial needs. This review uniquely integrates clinical evidence and lived experience to highlight how mainstreaming has transformed the delivery of hereditary cancer genetic counselling but not the need for specialist genetics expertise. Lynch syndrome illustrates how genomics can be integrated into routine cancer care while maintaining personalised counselling and family-centred follow-up. These principles are relevant across hereditary cancer predispositions and inform the future development of genetic counselling services.

The identification of a PRKACA duplication at 19p13.12 in a female with PPNAD and thyroid carcinoma after a 20-year diagnostic journey - Marjoleine F. Broekema; Florian Violon; Patricia Vaduva; Maartje Vogel; Nicole de Leeuw; Fenne Komdeur (Familial Cancer, 2026)
Rare pathogenic variants affecting components of the evolutionary conserved cAMP/protein kinase A (PKA) signalling pathway are implicated in a spectrum of adrenocortical disorders. Germline inactivating PRKAR1A variants leading to constitutive PKA activation, underlie primary pigmented nodular adrenocortical disease (PPNAD) in Carney complex. More recently, several patients with PPNAD and other types of bilateral nodular adrenal disease (BNAD) have been diagnosed with rearrangements in chromosome 19 at band p13.12, resulting in copy number gains of the entire PRKACA gene. Here, we report the identification of a 19p13.12 rearrangement, resulting in a duplication of the PRKACA gene, in a 32-year-old female from whom the genetic aetiology remained unknown for 20 years. Furthermore, we provide an updated overview of patients with PRKACA germline copy number gains that have previously been reported in the literature.

Opportunities to improve detection of genetic predisposition for ovarian cancer applying the Tumor-First workflow - Vera M. Witjes; Joanne A. de Hullu; Angela van Remortele; Lilian Vreede; Michiel Simons; Nicoline Hoogerbrugge; Marjolijn J. L. Ligtenberg (Familial Cancer, 2026)
Genetic testing in ovarian carcinoma (OC) patients is very important for patients and their relatives. The Tumor-First workflow uses a tumor DNA test to stratify germline testing for hereditary cancer predisposition as well as treatment options with PARP inhibitors. This workflow is adopted and successfully implemented nationwide. Here, we evaluated recent tumor DNA testing rates in the Netherlands to identify untested OC patient groups and optimize tumor DNA testing rates. OC patients diagnosed in 2023 or 2024 were selected from the Netherlands Cancer Registry. We analyzed patient characteristics associated with the likelihood of tumor DNA testing using multivariable logistic regression. Tumor-First testing was performed for 1765 out of the 2221 (79%) OC patients. Patients diagnosed with advanced stage OC were more likely to receive tumor DNA testing (OR = 2.5, p < 0.001) than those with low-stage disease. Compared with patients who underwent surgery as primary treatment, those who received chemotherapy or no primary treatment were less likely to be tested (OR = 0.21 and OR = 0.07, respectively, p < 0.001). Patients who died within 100 days were less likely to receive testing (OR = 0.57, p = 0.003). Patients without resection after diagnosis on biopsy/cytology had the lowest Tumor-First testing rates (58% vs. 87–95%, χ2 p < 0.001). Tumor-First testing rates are high. However, OC patients that do not undergo a resection are less likely to undergo testing. With these data strategies to identify hereditary cancer predisposition in patients and their relatives can be further improved.

Routes to colorectal cancer in Lynch syndrome: a decade of molecular and clinical insights converging on Schrödinger’s cat - Aysel Ahadova; Fatima Fayyaz; Leon Marin Grez; Hendrik Bläker; Matthias Kloor (Familial Cancer, 2026)
Colorectal cancer (CRC) development in Lynch syndrome (LS) has long been regarded to follow an adenoma-carcinoma sequence accelerated in comparison to microsatellite-stable (MSS) CRC development. Yet, several clinical observations challenged this hypothesis, most notably the persistently high CRC incidence under colonoscopy surveillance, a non-measurable benefit from shorter screening intervals, and substantial differences in cancer risk between carriers of the different mismatch repair (MMR) genes. Advances in the last decade have produced new hypotheses, highlighting the distinct biology of LS CRC and unravelling several co-existing pathways to cancer. Alongside the genomic heterogeneity, the immunogenic load created by the accumulation of frameshift mutations imposing selective pressure and leading to immune evasion, appears to be a critical step for cancer manifestation. We discuss potential clinical implications of these advances in understanding CRC pathogenesis for cancer prevention in LS and outline open questions that remain.

Mainstream and fast-track genetic testing in pancreatic cancer patients and its impact on treatment: our experience in a tertiary hospital in Spain - M. Bringas; I. Echavarría; C. Polo; N. Jiménez-Alduán; C. Flores; A. Muñoz; L. Ortega; G. Torres; J. Soto-Alsar; A. Calvo; P. García Alfonso; J. A. Pajares; et al. (Familial Cancer, 2026)

Brief report: attitudes and barriers toward genetic testing in pleural mesothelioma: a nationwide Italian survey - Luigi Cerbone; Matteo Perrino; Federica Grosso; Monica Ganzinelli; Giuseppe Lo Russo; Giulia Pasello; Paolo Andrea Zucali; Giovanni Luca Ceresoli; Mario Occhipinti; Marika Sculco (Familial Cancer, 2026)
Pleural mesothelioma (PM) is a malignancy with a relevant genetic component, with germline mutations identified in up to 12% of cases. International guidelines recommend universal germline testing; however, its implementation in routine clinical practice remains inconsistent. This nationwide survey aimed to assess current clinical practice, attitudes, and barriers related to genetic testing among Italian specialists within the Mesothelioma Team Italy (MET-I) network. A 24-item questionnaire was distributed to MET-I members in 2025, exploring access to testing, clinical use, and perceived obstacles to both germline and somatic DNA sequencing. Forty-five physicians responded (53.6%). Although access to germline testing was relatively high (77.8%), only 6.7% of respondents routinely recommended it. Conversely, somatic NGS was widely available (95.6%) and primarily used for clinical trial screening (66.7%). The main barriers to germline testing included costs (62.2%), limited access to genetic counseling (51.1%), and insufficient physician awareness (48.8%). Despite the availability of genetic testing technologies, germline genetic testing in PM is underutilized in Italy.

Impact of updated NCCN guidelines on clinical management and risk communication for CHEK2 p.I157T carriers in breast cancer - Emma A. Kell; Michael P. Mullane; Jennifer L. Geurts; Brenda Ramczyk; Tessa M. Bachinski (Familial Cancer, 2026)

Clinical and surveillance outcomes of the TP53 c.1000G > C (p.Gly334Arg) variant - Yehudit Peerless; Rinat Bernstein-Molho; Iris Kventsel; Zehavit Frenkel; Lilach Levi; Inbal Kedar; Aviad Zick; Tamar Peretz; Yael Goldberg; Naama Halpern (Familial Cancer, 2026)
Background Germline TP53 pathogenic variants are classically associated with Li-Fraumeni syndrome, although penetrance and tumor spectrum vary substantially across specific alleles. The Ashkenazi Jewish TP53 c.1000G > C (p.Gly334Arg) variant has been reported as a lower-penetrance, later-onset cancer predisposition allele, but its clinical classification and penetrance remain subjects of ongoing discussion. Consequently, the optimal surveillance approach for carriers remains uncertain, and real-world surveillance outcome data are limited. Methods We performed a retrospective descriptive study of heterozygous TP53 p.Gly334Arg carriers followed at two Israeli hereditary cancer clinics between 2021 and 2025. Clinical records were reviewed for demographic data, personal and family cancer history, and surveillance outcomes. Whole-body magnetic resonance imaging (WB-MRI) findings were analyzed for carriers who underwent serial surveillance. Results Eighteen carriers from five families were identified, all of Ashkenazi Jewish ancestry. Seven of 18 carriers (39%) had a personal history of malignancy. Breast cancer was the most common malignancy, occurring in four women, all diagnosed after age 50; available pathology showed hormone receptor-positive disease. No pediatric malignancies were observed, and none of the carriers met classic or Chompret clinical criteria for Li-Fraumeni syndrome. Ten carriers underwent serial WB-MRI surveillance, totaling 36 examinations (mean 3.6 per patient). No malignancies were detected. However, surveillance generated nine abnormal findings (0.25 per scan), all false positives, including one that led to invasive procedures. Conclusions In this clinic-based cohort, TP53 p.Gly334Arg was observed in association with a later-onset, potentially lower-penetrance cancer phenotype and low short-term surveillance yield. These findings support phenotypic heterogeneity among TP53 variants and raise questions regarding the optimal intensity of surveillance in this population; however, current data are insufficient to support modification of existing TP53 surveillance protocols. Larger multicenter studies with longer follow-up are needed to define penetrance and guide genotype-informed management.

Breast cancer phenotypes in carriers of pathogenic POT1 variants - Tal Hadar; Aasem Abu Shtaya; Rinat Bernstein-Molho; Marina Eskin-Schwartz; Inbal Kedar; Tamar Peretz-Yablonsky; Shiri Shkedi-Rafid; Rinat Yerushalmi; Aviad Zick; Gili Reznick-Levi; Tanir Allweis; Yael Goldberg (Familial Cancer, 2026)
Germline pathogenic variants (PVs) in POT1 , one of the shelterin complex genes, correlate with tumor predisposition, primarily with melanoma, hematologic malignancies, sarcoma, papillary thyroid carcinoma and glioma. Breast cancer (BC) risk has not been shown to be elevated. We analyzed BC occurrence and features in a cohort of 29 female PV heterozygotes, of whom 13/29 (45%) were diagnosed with BC. Data regarding genetic, clinical, pathologic, treatment, and outcome characteristics were extracted. Patients in our cohort harbored three different POT1 PVs; The c.233T > C Ashkenazi founder PV occurred in 11/13 (84.6%). Median age at first BC diagnosis was 54 years (range 44–72); no patient was diagnosed before the age of 40. Pathological subtypes varied; invasive ductal carcinoma was the most common. All primary tumors were estrogen receptor positive; one was HER2-enriched; no triple-negative cancers were observed. Stage at diagnosis varied: 6 of 10 tumors with known staging were stage 0 or I, and one patient presented with metastatic disease. Treatment approaches were diverse as clinically appropriate. After a median follow-up of 110 months, three second BC events occurred, with no BC-related mortality. Personal and family history of other malignancies were frequent. This is the first dedicated report describing BC phenotypes in POT1 PV heterozygotes. Our findings suggest that enhanced BC surveillance may be warranted in this population. Larger cohorts are needed to further characterize the clinicopathological features of BC in POT1 carriers, to define lifetime BC risk and determine whether BC-specific screening recommendations should be established for this group.

Lynch syndrome caused by a pathogenic SINE-VNTR-Alu (SVA) insertion in MSH2 gene identified by long-read DNA sequencing - Jihoon E. Joo; Khalid Mahmood; Mark Clendenning; Peter Georgeson; Romy Walker; Julia Como; Fiona Phillips; Bernard J. Pope; Steven Batinovic; Natalie Diepenhorst; Julie McDonald; Toni Rice; et al. (Familial Cancer, 2026)
Lynch syndrome, the most common hereditary cancer syndrome, is caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Identifying complex or structural MMR gene pathogenic variants can be challenging with short-read sequencing resulting in patients with unexplained MMR-deficient tumours. In this study, we report multiple members of a family who developed MSH2-deficient tumours where clinical multi-gene panel testing of the DNA MMR genes using short-read sequencing did not find a germline pathogenic variant. Oxford Nanopore Technologies adaptive sampling (ONT-AS) long-read sequencing, targeting 104 hereditary cancer genes, identified a shared ~ 3.2 kb SINE-VNTR-Alu (SVA) family F retrotransposon insertion within exon 12 of MSH2 in both the proband and her father. Segregation of this MSH2 SVA insertion by targeted PCR confirmed three additional family members as carriers, including a paternal uncle with three colorectal cancers and an MSH2-deficient sebaceous adenoma. Three of the five heterozygous carriers were cancer affected with at least one MSH2-deficient tumour each. This study demonstrates that long-read sequencing can identify structural variants that are missed by current short-read sequencing multi-gene panel testing, improving the diagnosis of Lynch syndrome. These findings support incorporating long-read sequencing into routine diagnostic workflows for patients with suspected Lynch syndrome following a negative germline test.

CGA-IGC 2025 Abstracts - Çağla Avcıoğlu (Familial Cancer, 2026)

Endoscopic detection of signet ring cell carcinoma in CDH1 carriers: a 15-year single-centre experience - Omar Salehi; Douglas Tjandra; Jadon Karp; Alex Boussioutas (Familial Cancer, 2026)
CDH1 pathogenic variant carriers are at high lifetime risk of hereditary diffuse gastric cancer (HDGC). Endoscopic surveillance is recommended for individuals who delay risk-reducing total gastrectomy, although detection of signet ring cell carcinoma (SRCC) remains challenging. No Australian cohort has reported real-world endoscopic performance with surgical correlation in this population. We performed a 15-year retrospective cohort study of adult CDH1 carriers undergoing esophagogastroduodenoscopy (EGD) at a tertiary familial cancer centre (2008–2023). Patients presenting with symptomatic invasive gastric cancer at initial endoscopy were excluded. Most EGDs were conducted as preoperative assessments prior to risk-reducing total gastrectomy, with a minority undertaken as longitudinal surveillance. Endoscopic findings, biopsy performance, surgical pathology, and postoperative outcomes were analysed. Eighty-two CDH1 carriers from 31 families underwent 136 EGDs (median 1 per patient). SRCC was detected endoscopically in 38 patients (46.3%), predominantly via random biopsies. Overall sensitivity for SRCC detection was 67.9%, with random biopsies outperforming targeted sampling. Most lesions were identified at the initial EGD. Sixty-nine patients (84.1%) proceeded to total gastrectomy; SRCC was confirmed in 56 (81.2%), with variable tumour burden (1–73 foci). Invasive disease beyond pT1a was uncommon (2.9%). Postoperative complications occurred in 43.5%, most frequently anastomotic strictures requiring dilatation; there were no procedure-related deaths. Although occult SRCC was common, invasive malignancy beyond pT1a was infrequent, suggesting that many intramucosal lesions may have a more indolent course than previously assumed. Detection of SRCC at endoscopy remains challenging; however, these findings support a more individualized, risk-adapted approach to CDH1 management. Longer-term prospective data are required to better define SRCC progression risk and guide decisions regarding surveillance and risk-reducing surgery.

Peutz-Jeghers Syndrome and lung cancer: does the risk meet the threshold for lung cancer screening? - Faizah Shareef; Mounica Konjeti; Samir Gupta; Jennifer M. Weiss (Familial Cancer, 2026)
Peutz-Jeghers Syndrome (PJS) is caused by germline pathogenic variants in the STK11 gene and is associated with elevated lifetime risks for several cancers, including lung cancer. Currently, no formal recommendations exist for lung cancer screening in PJS. This structured narrative review compares lung cancer risk in PJS with lung cancer risk in individuals currently eligible for screening based on age and smoking history. PubMed and Web of Science were searched from 1/1/1980 to 9/11/2023 using the terms “Peutz-Jeghers Syndrome” AND “Cancer.” Studies reporting lung cancer risk in PJS were included. Reported lung cancer risks were compared to 5-year, 10-year, and lifetime lung cancer risks in the general population based on age and pack-years of smoking. Seventeen studies were included. Across the studies, the incidence of lung cancer ranged from 0.8 to 13.3%. Studies that included lung cancer risk relative to the general population reported a relative risk range of 2.9–22.9. Cumulative risk was reported in 5 studies and surpassed 5% by age 60 (range 7 to 17%). Guidelines for low-dose CT (LDCT) lung cancer screening for individuals aged 50–80 with a smoking history of at least 20 pack-years are associated with a similar or higher threshold for lung cancer risk. The lifetime lung cancer risk for individuals with PJS is similar to current guideline-based risk thresholds for screening based on age and smoking status. Given their elevated lifetime risk, individuals with PJS may be candidates for LDCT for lung cancer screening and should be formally studied to elucidate the risks, benefits, and optimal implementation in this patient population.

Transitioning from the Prospective Lynch Syndrome Database (PLSD) to the International Lynch Syndrome Database (ILSD) - Mev Dominguez‑Valentin (Familial Cancer, 2026)

Expanding access to hereditary cancer genetic testing: a quality improvement initiative of mainstreaming in a diverse urban gynecology clinic - Alex Raghunandan; Lauren Davis-Rivera; Muhammad Danyal Ahsan; Isabelle R. Chandler; Steve Lopez; Amanda Laterza Ozarowski; Michelle Primiano; Christina Pardo; Ravi N. Sharaf; Melissa K. Frey (Familial Cancer, 2026)

The impact of international care networks on the clinical management of constitutional mismatch repair deficiency (CMMRD): a review of recent developments - Hans F. A. Vasen; Katharina Wimmer; Mariëtte van Kouwen; Léa Guerrini-Rousseau; Daniela Gattini; Lucie Stengs; Uri Tabori; Chrystelle Colas; Anirban Das (Familial Cancer, 2026)
Constitutional mismatch repair deficiency (CMMRD) is a rare and likely the most penetrant cancer predisposition syndrome caused by biallelic germline variants in a mismatch repair gene. Patients typically develop a spectrum of malignancies, including brain tumors, gastrointestinal cancers, and hematological neoplasms within the first two decades of life. Since its initial description in 1999, two international consortia, the International Replication Repair Deficiency Consortium (IRRDC) and Care for CMMRD (C4CMMRD), have been established to better understand the syndrome, leading to the creation of diagnostic guidelines and surveillance protocols. This review summarizes recent data on the CMMRD tumor spectrum and discusses the consortia’s updated diagnostic criteria and management guidelines, including novel blood-based assays for detecting constitutional microsatellite instability. Furthermore, we present the initial results and subsequent adjustments to international surveillance protocols. Finally, we discuss the demonstrated efficacy of immune checkpoint inhibitor (ICI) treatment, a key therapeutic advancement for CMMRD patients.

When screentime fails: initiative to improve completion of hereditary cancer genetic testing after telemedicine counseling - Isabel R. Murray; Muhammad Danyal Ahsan; Lauren Mitchell; Siena Gioia; Michelle Primiano; Amanda Laterza Ozarowski; Tina Karimaghaie; Steve Lopez; Ravi N. Sharaf; Melissa K. Frey (Familial Cancer, 2026)

Monoallelic NTHL1 p.(Gln90*) and cancer risk: evidence from a large Turkish cohort - Esma Ertürkmen Aru; Afife Büke; Hanife Saat; Taha Bahsi; Abdullah Sezer; Haktan Bağış Erdem (Familial Cancer, 2026)

Determinants of the quality of life of patients with NF2-related schwannomatosis and validation of the Dutch NFTI-QOL questionnaire - Annemijn L. Tops; Dorine Goemans; Emmelien Aten; Josefine E. Schopman; Radboud W. Koot; Hans Gelderblom; Jeroen C. Jansen; Erik F. Hensen (Familial Cancer, 2026)
NF2 -Related Schwannomatosis ( NF2 -SWN) is a rare tumor predisposition syndrome characterized by heterogeneous clinical manifestations that substantially impact quality of life (QOL). In this diverse patient population, a disease-specific QOL instrument is essential for both research and clinical decision-making. Insight into factors associated with QOL may further facilitate the tailoring of management strategies to individual patient needs. This study aimed to validate the Dutch version of the NF2 Impact on Quality of Life questionnaire (NFTI-QOL) and to identify factors associated with QOL in Dutch patients with NF2 . Following forward‑ and backward‑translation, the NFTI-QOL was administered to NF2 -SWN patients alongside the SF‑36, EQ‑5D and PANQOL. The NFTI-QOL was repeated after one week. Demographic and clinical data were extracted from medical records. To provide clinical context, questionnaires were also administered to patients with sporadic vestibular schwannoma (sVS). 64 NF2 -SWN and 51 sVS patients completed the questionnaires. The NFTI-QOL demonstrated good validity and reliability. In multivariate linear regression, dizziness (β = 2.533, p = 0.027) and facial weakness (β = 4.064, p = 0.008) were significantly associated with QOL, whereas hearing complaints were not. Surprisingly, overall QOL did not differ between NF2 -SWN and sVS patients, whereas patients with sVS even reported poorer hearing-related QOL. The Dutch NFTI-QOL is a reliable instrument for assessing QOL in NF2-SWN patients. Dizziness and facial weakness were associated with lower QOL, while hearing problems were not.

Von Hippel-Lindau disease: pathophysiological and clinical advances - S. J. van Alfen; K. van der Tuin; B. van de Kooij; T. P. Links; W. T. Zandee (Familial Cancer, 2026)
Von Hippel-Lindau (VHL) disease is a hereditary tumor predisposition syndrome caused by pathogenic germline variants in the VHL gene. Patients with VHL disease have an increased risk of developing characteristic VHL disease-associated lesions such as clear cell renal cell carcinoma, retinal angioma, central nervous system hemangioblastoma, pancreatic neuroendocrine tumors and pheochromocytomas. Loss of the VHL gene results in increased levels of the α-subunits of the heterodimeric hypoxia inducible factor (HIF). This drives transcription of HIF target genes which are involved in, amongst others: angiogenesis, erythropoiesis and iron metabolism. HIFs have been recognized as major drivers of VHL disease pathology and based on this notion, the HIF-2α inhibitor belzutifan was developed, which has marked a major breakthrough in the treatment of this disease. Belzutifan has now been approved for the treatment of a variety of VHL disease-associated lesions by the Food and Drug Administration and the European Medicines Agency. Interestingly, recent studies suggest that pVHL has functions beyond controlling HIF levels, and loss of these HIF-independent functions may further contribute to tumorigenesis in VHL disease. This review summarizes the most recent advances in pathophysiology, genotype–phenotype correlation, treatment guidelines, and potential future treatment options related to VHL disease.

Homozygous TP53 alterations: a case of a biallelic splice variant and a brief review of the literature - Said Furkan Yildirim; Ahmet Cevdet Ceylan (Familial Cancer, 2026)

RPS20 as a colorectal cancer predisposition gene: an integrated review of the literature and evaluation in 9738 cases and 161,403 controls - Anusha Amanullah; Juan Fernández-Tajes; Guler Gul; Steve Thorn; Ignacio Soriano; Joseph C. Ward; Kitty Sherwood; Ian Tomlinson (Familial Cancer, 2026)

Protecting the health of donor-conceived offspring - Anath A. Flugelman; Eli Y. Adashi; Zohar Levi (Familial Cancer, 2026)

Characterization of the molecular and clinical features of Multilocus Inherited Neoplasia Allelic Syndrome (MINAS) cases in the Turkish population - Mehmet Berkay Akcan; Ali Duru; Kadri Murat Erdoğan; Özge Özer Kaya; Selcan Keşan; Özgür Kırbıyık; Tuba Sözen Türk; Feyza Altunbaş Yalabık; Yaşar Bekir Kutbay; Özlem Anlaş; Merve Saka Güvenç; Altuğ Koç; et al. (Familial Cancer, 2026)

Colonoscopy findings and polyp pathology in CHEK2 carriers: a single center experience - Joshua Rosario; Sheng Zhou; Nicholas Bartell; Danielle Marino (Familial Cancer, 2026)

Association of gestational choriocarcinoma in a mother and Li-Fraumeni syndrome in her child: The result of a single event? - Juliette Sallé; Marie-Anne Brundler; Renee Perrier; Mary Brindle; Lucie Lafay-Cousin (Familial Cancer, 2026)

Genotypic and phenotypic characteristics of germline TP53 variant carriers: experience from two cancer genetic counseling units - Beatriz Grau Mirete; Asia Ferrández Arias; Paula Rodríguez Payá; María Valero Revert; David Sánchez Garcia; Mariano Martínez Marín; Javier-David Benítez-Fuentes; Isabel Chirivella González; Ana Beatriz Sánchez Heras (Familial Cancer, 2026)

Why patient organizations are important to improve care for people with Lynch syndrome - Jurgen Seppen (Familial Cancer, 2026)
Improving health care requires patient involvement. For people with Lynch syndrome, general and specific areas can be identified in which it is important for health care professionals to collaborate with patients to improve care. This collaboration is mutually beneficial; better care for the patients, reduction of work load and higher chance of funding of research proposals for health care professionals. Patient organizations are comprised of patients that are often more educated and motivated to participate in discussions and workshops. In addition, patient organizations have access to a network of patients that can provide a broad overview of the needs and requirements of this group. Thus, patient organizations are the partners of choice in the collaboration of health care providers and patients. In this commentary, I outline the areas in which physicians and patients should collaborate; Providing information, research and clinical trial design, and psychological care and peer support.

Personalized risk estimates of advanced neoplasia development in individuals with a family history of colorectal cancer - Marjolein J. E. Greuter; Eddymurphy U. Akwiwu; Simone D. Hennink; Tanya M. Bisseling; Marcel B. W. Spanier; Iris D. Nagtegaal; Karen Canfell; Evelien Dekker; Thomas Klausch; Iris Lansdorp-Vogelaar; Monique E. van Leerdam; Nicoline Hoogerbrugge; et al. (Familial Cancer, 2026)
To optimize surveillance in individuals with a family history (FH) of colorectal cancer (CRC), knowledge on the incidence rate of non-advanced adenomas (nAAs) and their progression rate to advanced neoplasia (AN) is crucial. We jointly estimated personalized adenoma incidence and progression rates using a novel statistical approach. We used data of individuals with ≥ 1 first-degree relative with CRC who underwent ≥ 2 colonoscopies ( n = 876 individuals; n = 2384 colonoscopies). Interval-censored data on timing and yield (no adenomas/nAA/AN) of each colonoscopy were available. nAA incidence and progression time from nAA to AN were estimated using a Bayesian progressive three-state model. Over a median follow-up of 6 years (interquartile range 5–6), 60 (6.8%) individuals developed AN (2 CRC, 58 AA) while 246 (28.1%) developed a nAA. The 5-year risk of developing nAA from baseline was estimated to be 29% (95% Crl: 21–39%). This risk was significantly associated with age and FH type. Estimated risk of progressing to AN within 5 years since nAA onset was 29% (95% Crl: 21–39%), and was significantly associated with having advanced adenomas at baseline. This resulted in a 5-year risk of transitioning from ‘no adenomas’ to AN of 7% (95% Crl: 5–9%). We showed that only 7% of individuals develop AN (primarily AAs) within the current 5-year colonoscopy surveillance interval. Future studies should evaluate whether this relatively low risk justifies slight extension of the surveillance interval or the use of fecal testing to guide colonoscopy timing. Furthermore, surveillance intensity could potentially be tailored based on age and FH.

Impaired glucose tolerance in women with BRCA1 versus BRCA2 pathogenic or likely pathogenic variants: Results from a prospective cohort study - Giovanni Grandi; Claudia Piombino; Giovanna Sighinolfi; Elena Barbieri; Marta Venturelli; Chiara Melotti; Rebecca Lippi Bruni; Valentina Grisendi; Riccardo Cuoghi Costantini; Mina Grippa; Emma Zattarin; Elena Tenedini; et al. (Familial Cancer, 2026)
Background Estrogens exert a beneficial effect on metabolism. Women carrying BRCA likely pathogenic/pathogenic variants (LP/PV) are at increased risk of premature menopause and may therefore be at higher risk of developing metabolic disorders later in life. In this single-center prospective cohort study, we investigated whether the specific BRCA mutation ( BRCA 1 vs. BRCA 2) has a differential impact on metabolism in women. Methods Eligible participants were BRCA LP/PV carriers who were premenopausal or underwent menopause –either natural or iatrogenic– within the 5 years prior to enrollment. Blood samples for lipid and glucose panels were obtained every 6 months, for a total of four time points. Body composition variables were evaluated at baseline and at the final follow-up using bioimpedance analysis. Glucose tolerance was assessed using the homeostatic model assessment for insulin resistance (HOMA-IR). Associations between lipid and glucose profile and patient characteristics were evaluated using univariable and multivariable linear regression models. Results Fifty-seven BRCA1 and 58 BRCA2 LP/PV carriers were included in the final analysis. At baseline, BRCA1 LP/PV carriers had a higher body mass index (BMI) (27.3 vs. 24.6 kg/m 2 , p = 0.01) and higher fat mass (27.3 vs. 21.9 kg, p = 0.013) than BRCA2 LP/PV carriers. Insulin levels and HOMA-IR were consistently higher in BRCA1 than in BRCA2 LP/PV carriers at all time points, and this difference was not attributable to age, BMI, menopausal status, risk-reducing salpingo-oophorectomy, previous chemotherapy or use of cholesterol-lowering agents. The lipid profile was similar between the groups, although BRCA1 LP/PV carriers showed a tendency toward a less favorable profile (higher LDL and lower HDL). Conclusions These prospective results suggest that BRCA1 LP/PV carriers might have impaired glucose tolerance and a greater tendency toward insulin resistance compared with BRCA2 LP/PV carriers: this first report needs further independent confirmations from other cohorts.

Factors influencing uptake of risk-reducing mastectomy among unaffected Israeli BRCA1/BRCA2 pathogenic variant carriers - Yael Laitman; Karin Aharon; Talia Schloss; Libby Margolin; Eitan Friedman (Familial Cancer, 2026)
Women harboring pathogenic variant (PV) in the BRCA1 or BRCA2 genes (= BRCA ) have an elevated lifetime risk for breast cancer (BC). One of the main options for active BC risk reduction is bilateral risk-reducing mastectomy (RRM). Understanding the factors influencing that decision is important for genetic-counselling and risk mitigation strategy planning. A structured questionnaire was circulated to BRCA carriers, members of the Good Genes NGO in Israel. Data on RRM uptake and timing, factors previously reported to be associated with decision to undergo RRM (e.g., psychosocial, family history, counselling/health-system factors) were obtained. Comparison between carriers who elected to undergo RRM with those who opted for early detection schemes were performed using logistic regression and chi square statistical analyses. Of cancer free women ( n = 391), 272 (69.6%) elected to adhere to the recommended surveillance scheme and 119 (30.4%) elected to undergo RRM. The major reasons for electing RRM over surveillance were active BC risk reduction (4.96 ± 0.23), fear of developing BC (4.86 ± 0.50), and having at least one relative with BC diagnosed under age 45 years. Support group discussions emerged as a stronger determinant of RRM uptake than primary care physician or religious guidance. In conclusion, among healthy Israeli BRCA carriers the decision to undergo RRM was influenced by a complex interplay of factors—active BC risk reduction, fear of cancer diagnosis in the context of having one relative with early onset BC and support group discussions were the major drivers of RRM in Israeli BRCA1 carriers.

Association between breast cancer, pancreatic cancer, and melanoma in a CDKN2A variant common in the Hispanic population - Emily S. Parkhurst; Jaime L. Natoli; Xing Wei; Darwin A. Luna; Timothy J. Maarup (Familial Cancer, 2026)

Optimal upper gastrointestinal surveillance strategies for gastric, small bowel and pancreatic cancer detection in Lynch syndrome - Tim Marwitz; Aleksander M. Bogdanski; Robert Hüneburg; Monique E. van Leerdam (Familial Cancer, 2026)
Lynch syndrome is an autosomal dominant cancer predisposition syndrome and the most common cause of hereditary colorectal cancer. In addition to colorectal cancer, it confers substantially increased risks for several extracolonic malignancies. While there is broad consensus regarding the effectiveness of endoscopic colorectal surveillance, recommendations for surveillance of gastric, small bowel, and pancreatic cancers vary considerably among guidelines issued by leading professional societies. These discrepancies largely reflect the limited availability of robust, high-quality evidence. In this narrative review, we summarize the cancer risks for gastric, small bowel, and pancreatic malignancies in Lynch syndrome carriers, discuss recent studies evaluating the outcomes of surveillance strategies, and provide an overview of current guideline recommendations. Furthermore, we highlight emerging approaches that may enhance surveillance strategies in the future. In recent years, increasing research efforts have focused on surveillance for less frequent Lynch syndrome-associated malignancies, however, prospective data from large, well-characterized cohorts remain scarce. Such data are essential to harmonize existing guidelines and to enable the development of personalized surveillance strategies for individuals affected by Lynch syndrome.

Familial risks in prostate cancer between brothers and half-brothers as clues to germline genetic and environmental causes - Kari Hemminki; Frantisek Zitricky; Kristina Sundquist; Jan Sundquist; Asta Försti; Akseli Hemminki; Otto Hemminki (Familial Cancer, 2026)
Swedish family and cancer data constitute the largest source on familial cancer in the world. We analyze here familial risks in prostate cancer (PC) with focus on multiple affected brothers and comparation of full-brothers to maternal and paternal half-brothers. Age-specific incidence and standardized incidence ratios (SIRs) were calculated for PC in brothers. Curves for relative risk (RR) by diagnostic age were plotted for risk distributions. A total of 115,066 PCs were diagnosed in 1.2 million men. Familial SIR for full brothers was 2.23, for maternal half-brothers it was 1.92 and paternal half-brothers was 1.34. Considering SIRs with least possible detection bias (7+ years after first brother’s diagnosis) the above SIRs were 2.06, 1.66 and 1.41. SIRs in full brothers increased stepwise by the number of affected brothers reaching 21.33 when 6 brothers were affected. Age-RR curves for two affected brothers declined evenly from RR 2.8 at age 45 to below 2.0 at age 80. When four or more brothers were affected, a discrete high-risk peak (RR 4–7) was detected between ages 60 and 69. Data on full-brothers and half-brothers indicate that familial risk in PC is largely genetic which is also supported by discrete RR peaks in high-risk families at ages matching preferential penetrance age for known predisposition genes of PC. Familial risk increased already when two brothers were affected calling for clinical vigilance concerning family history. Family history should deserve a place as an inclusion criterium in schemes for PC screening.

Biallelic germline MBD4 mutations predispose to colorectal polyposis, hypermutated AML, and schwannomas - Julia Cooper; Brittany L. Stewart; Lauren Bokovitz; Hetty Carraway; Sudipto Mukherjee; David Liska; Sumithira Vasu; Harry Lesmana; James S. Blachly (Familial Cancer, 2026)
Biallelic pathogenic variants in the MBD4 gene have recently been associated with an autosomal recessive cancer predisposition syndrome deemed “ MBD4 -associated neoplasia syndrome (MANS)”. Early reports of individuals with MANS highlight the propensity to develop young onset colorectal polyposis and hyper-mutated acute myeloid leukemia (AML). In the following case series, we present four patients with MANS from three families with polyps and AML, as well as additional features previously less described, such as schwannoma and thyroid cancer. This series increases the total number of reported cases by 27%, with the intention of achieving a more robust understanding of the full phenotypic spectrum of MANS.

Lynch syndrome integrative epidemiology and genetics (LINEAGE): rationale for cohort design - Swati G. Patel; Holli A. Loomans-Kropp; Zachariah H. Foda; Bryson W. Katona; Suzi Birz; Carol A. Burke; Jordan Clawson; Brian Furner; Camille Hochheimer; Elizabeth Magnan; Luigi Ricciardiello; Harminder Singh; et al. (Familial Cancer, 2026)

Trends in breast reconstruction for BRCA1/2, PALB2 and other high penetrance germline pathogenic variant carriers undergoing risk reducing mastectomy - Amel Melanson; Marya Alsuhaibani; Alex Viezel-Mathieu; Tassos Dionisopoulos; Mark Basik; Jean Francois Boileau; Karyne Martel; Ipshita Prakash; Sarkis Meterissian; Joshua Vorstenbosch; William D. Foulkes; Stephanie M. Wong (Familial Cancer, 2026)

From “who to test” to “who benefits”: equity-by-design guardrails for prostate cancer germline testing at scale - M. Vijayasimha; M. Srikanth (Familial Cancer, 2026)

Five-year psychological impact and surveillance compliance in the Australian Pancreatic Cancer Screening Program - Tanya M. Dwarte; David K. E. Chan; Nick Olsen; David B. Williams; Anthony J. Gill; Alina Stoita (Familial Cancer, 2026)
Evidence of benefit for pancreatic ductal adenocarcinoma (PDAC) surveillance is accumulating, including earlier staging, extended survival, and improved psychological function. This study aimed to assess the 5-year psychological impact of high-risk PDAC surveillance, performed at St Vincent’s Hospital, Sydney, Australia. Participants were offered annual endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI), with frequency increasing if clinically indicated. The impact of event scale (IES), comprising intrusion and avoidance subscales, and the psychological consequences questionnaire (PCQ), which assesses emotional , physical and social domains, were administered at baseline, 1-month, 1-year and 5-years post-baseline EUS. Generalized linear mixed-effects models were used to assess for differences in reported outcomes. Of the 143 participants under surveillance, 108 underwent annual investigations, and 35 had one or more episode(s) of intensified surveillance. Overall, screening compliance was high, though understandably, increased deferrals occurred during COVID-19 pandemic restrictions. Two participants were diagnosed with pancreatic neoplasms and half had pre-malignant pancreatic lesions that remained stable (n = 45) or showed progression (n = 28). There was a significant reduction in IES intrusion and an increase in positive PCQ emotional, physical and total scores at 5-years. Negative PCQ scores remained stable compared to baseline. There was no difference in IES, negative PCQ or positive PCQ scores based on EUS/MRI findings. Individuals undergoing intensified surveillance reported significantly lower positive PCQ physical and total scores, but there was no difference in negative PCQ or IES scores. These data provide reassurance regarding the acceptability and psychological safety of PDAC surveillance, despite frequent abnormal findings and intensified investigation.

Early detection of urological malignancies in Lynch syndrome: a systematic review - B. H. J. Doornweerd; M. W. Rasmussen (Familial Cancer, 2026)
Lynch syndrome predisposes to multiple cancer types, including urological malignancies. However, no evidence-based recommendations for surveillance of urological malignancies currently exist. In this systematic review, we aim to describe the current evidence regarding surveillance for these cancers. A systematic literature search was conducted using MEDLINE, searching for urological malignancies, Lynch syndrome, and surveillance including the results of the surveillance methods. Sensitivity and specificity were calculated, when possible, preferably for pooled data from each surveillance method. The risk of bias was assessed using the Newcastle–Ottawa Scale. After full text-screening, nine studies published in 2008–2025 met the inclusion criteria, including two on prostate cancer and seven on urothelial cancer. Prostate cancer-antigen (PSA) surveillance led to 38 prostate cancer diagnoses in 865 individuals with Lynch syndrome, with 71% being clinically significant prostate cancers. In 1564 individuals, 11 urothelial carcinomas were diagnosed by different surveillance methods and 15 diagnoses were missed. Sensitivity of urinalysis, urine cytology, urine MSI, and CT and cystoscopy was 11%, 30%, 100%, and 100% respectively. Specificity was 90%, 97%, 99%, and 100% respectively for these methods. Further data is needed but for prostate cancer surveillance PSA shows promise, while for MSH2 carriers at least, urine microsatellite instability analysis shows promise as a urothelial cancer surveillance test.

Correction: Hereditary gynecological cancer management in women with Lynch syndrome: a survey across Europe - Kevin J. J. Kwinten; Joanne A. de Hullu; Helen Bolton; Monique M. A. Brood-van Zanten; Valentina Chiappa; Stefan Cosyns; Sergi Fernandez-Gonzalez; Angelique Flöter Rådestad; Sophie Frank; Rieke Gellner; Susanne Housmans; Nina Kovacevic; et al. (Familial Cancer, 2026)

Case report: Onychopapilloma in a patient with BAP1 tumor predisposition syndrome—a useful clinical marker? - Emilie Sjøstrøm; Lise Barlebo Ahlborn; Elisabeth Victoria Eliesen; Karin Wadt; Ulrikke Lei; Anna Byrjalsen (Familial Cancer, 2026)
The BAP1 gene encodes a tumor suppressor protein implicated in BAP1 tumor predisposition syndrome ( BAP1 -TPDS), a hereditary condition associated with an increased risk of uveal and skin melanoma, mesothelioma, and renal cancer. In this case report, we describe a male patient diagnosed with mesothelioma carrying a germline BAP1 variant. The patient exhibited severe nail abnormalities affecting all ten fingernails and several toenails. To our knowledge, the association between onychopapilloma and pathogenic germline BAP1 variants has only been reported once in the literature. The patient had experienced nail abnormalities since adolescence. Based on these findings, we propose that polydactylous onychopapilloma may serve as a clinical marker of BAP1 -TPDS in otherwise asymptomatic individuals, and could potentially aid in early identification of at-risk carriers.

Dual radiation-induced sarcomas after breast cancer in a TP53 variant carrier - Riccardo Ricci; Patrice Peyrat; Armelle Dufrene; Giovanni Papa; Maria Adele Dammacco (Familial Cancer, 2026)

Vaccine strategies for cancer prevention in Lynch syndrome: the potential of dendritic cell-based therapy - Romy N. Kuipers; Mark A. J. Gorris; Cristina Bayó; Tom Hofland; Daniel Benítez Ribas; Georgina Flórez Grau; Nicoline Hoogerbrugge; Joaquin Castillo; Francesc Balaguer; Tanya M. Bisseling; Gerty Schreibelt; I. Jolanda M. de Vries (Familial Cancer, 2026)
Cancer vaccines offer a promising strategy for cancer prevention, particularly in hereditary cancer syndromes such as Lynch syndrome (LS). LS is characterized by a high lifetime risk of developing various malignancies due to defects in DNA mismatch repair, leading to an accumulation of mutations, particularly frameshift insertion/deletions (indels) within microsatellite loci. These indels create shared tumour-specific neoantigens, which are unique to LS and can be recognized by the immune system and trigger cancer cell killing. Importantly, these neoantigens are also present in precancerous lesions, making LS an ideal target for immune-interception strategies aimed at prevention. Over the years, a variety of vaccine designs targeting different antigens along with a range of delivery platforms have been explored for different types of tumours, each with its own advantages and limitations. In this review, we provide an overview of the key antigens and delivery platforms used in cancer preventive vaccine development for LS, evaluate their limited clinical outcomes to date, and explore the future directions of preventive vaccine immunotherapy. A particular focus is placed on the promising potential of dendritic cell vaccination therapy as a future approach in this field.

Frequency of bilateral prophylactic and contra-lateral risk-reducing mastectomies in women with germline PALB2 variants - Giovanni Corso; Carlo La Vecchia; Andrea Polizzi; Francesca Magnoni; Giuliarianna Abruzzese; Susanna Di Silvestre; Filippo Pesapane; Luca Nicosia; Giorgio Bogani; Mattia Intra; Paolo Veronesi; Viviana Galimberti (Familial Cancer, 2026)

Retraction Note: Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis - Dejana Braithwaite; Jon Emery; Fiona Walter; A. Toby Prevost; Stephen Sutton (Familial Cancer, 2026)

Factors influencing public willingness to participate in population-based hereditary cancer genetic testing: a qualitative study of public preferences - Diego R. Sanchez-Vazquez; Jonathan Avery; Whitney Qualls; Colene Bentley; Helen McTaggart-Cowan; Julianne McLeod; Lesa Dawson; Stuart Peacock (Familial Cancer, 2026)

A new c.681dup RUNX1 variant in familial leukemia - Maria Crocioni; Carlotta Nardelli; Anair Graciela Lema Fernandez; Valentina Bardelli; Valentina Pierini; Caterina Matteucci; Eloise Beggiato; Matteo Olivi; Valentina Vigliani; Alessandra Pelle; Giuseppe Lanzarone; Cristina Mecucci (Familial Cancer, 2026)
Constitutional RUNX1 gene variants are associated with Familial Platelet Disorder (FPD) and predispose to a variety of hematological malignancies, included Acute Myeloid Leukemia (AML) and, albeit less frequently, Acute Lymphoblastic Leukemia (ALL). In this study, we report on a proband with primary diagnosis of AML, followed by T-ALL after transplant, and a positive familial history for leukemia over three generations. A new heterozygous germline pathogenic RUNX1 (c.681dup, p.(Leu228ThrfsTer33)) variant was found in the proband and his affected mother.

Hereditary gynecological cancer management in women with Lynch syndrome: a survey across Europe - Kevin J. J. Kwinten; Joanne A. de Hullu; Helen Bolton; Monique M. A. Brood-van Zanten; Valentina Chiappa; Stefan Cosyns; Sergi Fernandez-Gonzalez; Angelique Flöter Rådestad; Sophie Frank; Rieke Gellner; Susanna Housmans; Nina Kovacevic; et al. (Familial Cancer, 2026)
We aim to compare clinical practices in the gynecological management of women with Lynch syndrome across Europe and assess the need for multidisciplinary gynecological care for this high-risk population. European gynecologists involved in the clinical care of women with Lynch syndrome were invited to complete a cross-sectional survey regarding their clinical practices and organization of care. All participating gynecologists were based in hospitals that are members of the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). A total of 33 gynecologists (57%) from 25 unique hospitals across 12 countries participated in the survey. National guidelines on the gynecological management of women with Lynch syndrome were absent in a significant number of European countries. Local multidisciplinary team meetings were available in 61% of hospitals. Considerable heterogeneity was reported in the organization of care, as well as in surveillance, prevention, and treatment strategies. Standardized European guidelines for the gynecological care of women with Lynch syndrome are warranted to promote uniformity. Gynecologists specialized in hereditary cancer should take the lead in developing and implementing these guidelines. Hospitals managing women with Lynch syndrome should have the resources to organize multidisciplinary team meetings, which are crucial for the effective implementation of these guidelines and the improvement of personalized care.

Re-evaluating hereditary breast and ovarian cancer risk: clinical impact of updated multigene panel sequencing and genetic counseling - Julie Isabelle Plougmann Gislinge; Anna Byrjalsen; Klara Vinsand Naver; Helle Vibeke Clausen; Pernille Ravn; Kresten Rubeck Petersen; Karin A. W. Wadt (Familial Cancer, 2026)
An increased lifetime risk of ovarian cancer is observed among women with a family history of ovarian cancer, with or without breast cancer, as well as among carriers of pathogenic germline variants in ovarian cancer (OC) predisposition genes. Over the past two decades, additional OC–associated genes beyond BRCA1/2 have been identified, highlighting the need for updated genetic evaluation in women previously classified as high-risk without a known PV to ensure correct diagnosis and prevent overtreatment. This retrospective, quality assurance cohort study aimed to evaluate whether updated multigene panel sequencing and genetic counseling improve risk stratification. All women enrolled in the OC surveillance program at Copenhagen University Hospital Herlev between 2018 and 2023 and received counseling prior to the implementation of the revised 2017 guidelines in Denmark, were included. Among 674 women (median age 40.9), 174 had a BRCA1 PV, 168 had a BRCA2 PV, 55 had PVs in moderate-risk genes, and 277 were enrolled based on family history of OC ± BC alone. Of these 277, 216 (78%) underwent updated genetic testing and counselling; 165 (76%) had no increased risk of OC and were released from gynecological surveillance. Over a mean follow-up of 48 months, none developed OC, and one developed BC, corresponding to a negative predictive value of 99% for the updated risk assessment. Updated genetic testing and counseling significantly improve risk stratification in women previously classified as increased risk of OC based solely on family history. This supports re-evaluation of at-risk women and families to guide appropriate surveillance, reduce unnecessary follow-up and interventions, and align clinical practice with evolving guidelines.

Cascade testing as the missing link in cancer prevention among Lynch syndrome families - Lea Godino; Giulia Erini; Giovanni Innella; Sara Miccoli; Simona Ferrari; Pamela Magini; Luca Caramanna; Martina Preite; Veronica Simoni; Daniela Turchetti (Familial Cancer, 2026)

Prevention strategies for hereditary gynaecological cancer in Lynch syndrome - Kevin J. J. Kwinten; Jean-Ellen Johnson; Anne M. van Altena; Nicoline Hoogerbrugge; Emma J. Davidson; Joanne A. de Hullu (Familial Cancer, 2026)
Lynch syndrome is a hereditary cancer predisposition condition associated with an elevated lifetime risk of colorectal, endometrial, ovarian, and several other malignancies. This review provides an updated overview of evidence-based prevention strategies for gynaecological cancers in patients with Lynch syndrome. Risk-reducing hysterectomy with bilateral salpingo-oophorectomy is the most effective intervention for lowering cancer incidence and mortality, but is associated with surgical morbidity and requires careful consideration of reproductive plans and the adverse consequences of premature menopause. Gynaecological surveillance using transvaginal ultrasound and endometrial biopsy is widely implemented as an alternative; however, available evidence is heterogeneous and indicates no benefit in reducing mortality. Novel approaches—such as biomarker-based detection using DNA methylation analysis of cervicovaginal samples, liquid biopsy techniques, and microbiome profiling—offer promising, non-invasive alternatives but require prospective validation in Lynch-specific populations. Chemoprevention with hormonal agents and aspirin may reduce cancer risk, while vaccine-based prevention strategies are under active investigation. Adoption of a healthy lifestyle is recommended for overall health, although its impact on gynaecological cancer risk in Lynch syndrome remains uncertain. Future research should prioritise prospective trials to establish optimal cancer prevention protocols, validate novel biomarkers and preventive cancer vaccine strategies, and evaluate the long-term effectiveness, acceptability, and cost-effectiveness of combined preventive approaches to improve outcomes in this high hereditary-risk population.

Endoscopic prediction model for detecting advanced rectal polyps after ileorectal anastomosis in familial adenomatous polyposis: a dual-center retrospective study - Zhilin Liu; Xingjie Gao; Shuling Chen; Linfu Zheng; Binbin Xu; Gaozhen Deng; Wen Wang; Kun Lin; Chushu Li; Zhou Ye; Dazhou Li (Familial Cancer, 2026)

Genetic testing for hereditary breast and ovarian cancer in the Murcian population using a comprehensive NGS panel - Y. Mestre Terkemani; L. Rosado Jiménez; A. García Aliaga; M. D. Sarabia Meseguer; M. Marín Vera; J. A. Macías Cerrolaza; P. Sánchez Henarejos; M. R. García Hernández; M. Zafra Poves; B. Alvarez Abril; E. García Torralba; C. B. López Sánchez; et al. (Familial Cancer, 2026)

Uptake and timing of risk-reducing gynecologic surgery among individuals with Lynch syndrome identified via population screening - Jazmine L. Gabriel; Michelle Pistner Nixon; Olivia Steinmetz; Gina Rossi; Abigail Glynn; Lavanya Garnepudi; Annum Hayat; Beatriz Abello; Kaitlin Toal; Katrina M. Romagnoli (Familial Cancer, 2026)

Factors affecting compliance with pancreas surveillance in patients with familial/genetic risk - Emy Abou Sleiman; Hassan Sinan; Eun Ji Shin; Marcia Irene Canto; Michael Goggins (Familial Cancer, 2026)

Patient-derived outcome assessment of knowledge, communication, and management in those diagnosed with BAP1-tumor predisposition syndrome - Kelley Godwin; Joseph McElroy; Leigha Senter; Lindsey Byrne; Mohamed H. Abdel-Rahman (Familial Cancer, 2026)
Germline pathogenic variants in BAP1 are associated with BAP1 tumor predisposition syndrome ( BAP1 -TPDS), and an increased risk for different cancers and preneoplastic lesions. This study assessed the degrees of patient knowledge of BAP1 -TPDS, patient-reported sharing of their genetic test results and diagnosis, and the degree of compliance with current management guidelines. A survey was sent to individuals with a germline pathogenic/likely pathogenic variant in BAP1 who are enrolled in a research registry at The Ohio State University. Knowledge about BAP1 -TPDS was assessed utilizing a modified scale (KnowGene). Participants were asked about communication surrounding BAP1 -TPDS with family members, and their current cancer surveillance. Forty-two (55%) subjects completed the survey with 25 (60%) having strong 80% knowledge of the syndrome, and 33 (79%) having at least 60% knowledge. All participants reported sharing their genetic result or diagnosis with at least one family member, primarily their first-degree relatives. Most of the cohort had undergone some recommended surveillance for BAP1 -TPDS. In conclusion, BAP1 -TPDS subjects are knowledgeable about the syndrome phenotype, highly communicative about their diagnosis with family members, and follow some recommended surveillance. Capturing patient-reported outcomes of BAP1 -TPDS subjects is crucial for understanding their need for further education, resources, or support.

The gut microbiome as a biomarker and modifiable risk factor in Lynch Syndrome - Verona Sarena Colaco; Annemarie Boleij (Familial Cancer, 2026)
Lynch Syndrome (LS) is the most prevalent hereditary colorectal cancer syndrome, driven by germline mutations in DNA mismatch repair genes. Despite intensive colonoscopy surveillance, cancer risk among LS carriers remains highly variable, suggesting additional modifiers beyond genetics. Emerging evidence implicates the gut microbiome as a potential biomarker and modifiable risk factor in LS-associated carcinogenesis. This review synthesizes current findings on taxonomic and functional microbiome alterations in LS carriers, highlighting early dysbiosis characterized by depletion of butyrate-producing taxa and enrichment of virulent species such as pks + Escherichia coli , Fusobacterium nucleatum , and enterotoxigenic Bacteroides fragilis . These oncogenic microbes promote DNA damage, inflammation and epithelial hyperproliferation in the mismatch repair deficient context, accelerating tumorigenesis. Functional signatures such as colibactin genotoxicity appear more predictive than taxonomic diversity. However, methodological heterogeneity, small cohorts and lack of longitudinal data limit biomarker validation. Finally, we outline future research that should integrate multi-omics, spatial profiling and genotype-stratified designs to identify clinically actionable microbial signatures. Understanding microbiome and host interactions in LS could assist in improved risk stratification beyond current standard surveillance guidelines.

InSiGHT 2026 meeting: abstracts (Familial Cancer, 2026)

Improving care for Lynch syndrome patients: integrating surveillance into England’s national bowel cancer screening programme - Kevin J. Monahan; Stephanie X. Poo; Fiona Lalloo (Familial Cancer, 2026)
Quality assurance, timeliness and equity of access to colonoscopy for people with Lynch syndrome (LS) in England has historically been highly variable. The LS-Bowel Cancer Screening Programme (LS-BCSP) launched in July 2023, delivers high quality colonoscopy to the average-risk population, from colonoscopists who have undergone high-level accreditation, utilising the existing average-risk BCSP infrastructure. Eligible individuals have a genetic diagnosis of LS. Comprehensive retrospective diagnoses of LS in England (since the 1990s) were ascertained from 17 regional genetics services. The National Disease Registration Service (NDRS) developed a registry of eligible individuals, and a portal for prospectively diagnosed cases. An existing national screening IT framework was adapted to incorporate disease-specific clinical pathway information, linked to existing national guidelines. Nationally standardised training for BCSP teams was delivered to > 2000 staff from 64 national screening centres in 2023. By November 2024, 10,913 eligible individuals were identified, with 150–250 new diagnoses added each month. A historical backlog of > 1000 patients overdue colonoscopy surveillance was cleared by January 2024. Diagnostic outcomes of LS patients from the first two years of LS-BCSP will be available to facilitate evaluation of the successes and failures of the LS_BCSP. This evaluation will include diagnostic outcomes, stratified by demographic and socioeconomic status, genotype, measures of colonoscopy quality and regional variation. This novel programme includes complete ascertainment of the national LS population in England, without requirement for referral. Individuals with LS now have access to high-quality, timely colonoscopy through an accredited programme which is quality-assured along the entire pathway.

From theory to practice: improving Lynch syndrome recognition through evidence-based education - Silvia Sanduleanu-Dascalescu; Gabriel Dimofte; Han-Mo Chiu; Bogdan Cotruta; Stefan Morarasu; Hans Vasen (Familial Cancer, 2026)

Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant - Kristjan Ari Ragnarsson; Gloria Garcia; Jon Gunnlaugur Jonasson; Gudny Anna Arnadottir; Sigrun Edda Reykdal; Reynir Arngrimsson; Sigurdis Haraldsdottir; Jon Johannes Jonsson (Familial Cancer, 2026)
BAP1 tumour predisposition syndrome ( BAP1 -TPDS) is a hereditary cancer syndrome caused by heterozygous pathogenic germline variants in BAP1 . BAP1 -TPDS is associated with an increased risk for various malignant tumours, the core of which is uveal and cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. In BAP1 -TPDS, the majority of disease-causing BAP1 variants are null variants, although missense variants have been reported. We report a patient with BAP1 -TPDS caused by the novel germline BAP1 missense variant NM_004656.4:c.382G > A, p.(Gly128Arg). The patient developed BAP1 -inactivated melanocytic tumours, clear-cell renal cell carcinoma, and splenic hamartoma. An incidental splenic hamartoma was detected in existing tissue slides from the patient’s deceased first-degree relative, who was an obligate carrier for BAP1 -TPDS. In both splenic hamartomas, loss of BAP1 nuclear staining was detected in a subset of cells on immunohistochemistry. To our knowledge, this is the first report with immunohistochemical data supporting biallelic loss of BAP1 as a contributing step in the development of a splenic hamartoma in a patient with BAP1 -TPDS. It supports expanding the tumour spectrum of BAP1 -TPDS to splenic hamartoma and possibly other benign splenic tumours.

Misinterpreting the results: patient misconceptions about genetic cancer risk after obstetrical carrier screening - Alex Raghunandan; Sonali Iyer; Shayan Dioun; Jessica Scholl; Robin B Kalish; Michelle Primiano; Amanda Laterza Ozarowski; Ravi N Sharaf; Melissa K. Frey (Familial Cancer, 2026)

Does bilateral mastectomy affect clinical outcomes in BRCA1/2 mutation carriers with primary breast cancer? A systematic review and meta-analysis - Pedro Henrique de Souza Wagner; Gustavo Tadeu Freitas Uchôa Matheus; Hideki Zimermann Kamitani; Pedro Lucas Azevedo de Carvalho; Francisco Cezar Aquino de Moraes (Familial Cancer, 2026)

Mental- and physical health, and general well-being in patients with polyposis syndromes: a scoping review - Sophie Walton Bernstedt; Anna Jervaeus; Veronica Höiom; Kaisa Fritzell (Familial Cancer, 2026)
Polyposis syndromes are associated with an increased lifelong cancer risk in several organs as well as a commitment to regular examinations and risk-reducing surgery of healthy organs, which can be compared to living with a constant health threat. More recently conducted research on the topic is scarce, and, therefore, this scoping review synthesized data of existing research on mental and physical health and general well-being from the patients’ perspectives. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) was used. The search was conducted between January 2000 and October 2024, leading to the identification of 4138 studies. Of those, 39 studies met the inclusion criteria (1%), and of the 2214 included participants, 2108 had familial adenomatous polyposis. In order to analyze and synthesize relevant data, aspects of directed content analysis were applied. The findings show that patients exhibited mental and physical health in parity to population norms. However, feelings of vulnerability, anxiety, worry and fear, especially in younger participants were reported. In addition, decreased bowel and sexual function, food restrictions, body dissatisfaction, and physical attractiveness were evident. Regarding well-being, an altered lifestyle, work and social discrimination, insurance matters, concerns for family members and fertility were reported. Being female seemed to be related to mental health issues or vulnerability thereof. Appropriate screening tools, such as patient reported outcome measures (PROM), should be developed and implemented in a structured way to capture patients needs in clinical settings. Future research is needed for the rarer syndromes, represented to a limited extent in this review.

Single institution assessment of physician compliance and patient uptake with guideline directed aspirin therapy in the prevention of colorectal cancer in lynch syndrome - Alexandra Yudiski; Heather Rocha; Edward Liu; Matthew Dzeda; Olivia Granja; Nicholas Haynes; Hannah Woolley; Shane Conklin; Gabrielle Shermanski; Amanda Leicht; Thomas Morland; Kathie Wu; et al. (Familial Cancer, 2026)

Attenuated Li–Fraumeni syndrome with TP53 p.R181H in a Japanese patient with metastatic rectal adenocarcinoma: a case report - Yuki Kasahara; Masanobu Takahashi; Yoshifumi Kawamura; Yoko Aoki; Tetsuya Niihori; Maako Kawamura; Shinnosuke Yamamoto; Hidekazu Shirota; Ken Saijo; Hiroo Imai; Keigo Komine; Kota Ouchi; et al. (Familial Cancer, 2026)

Hereditary ovarian cancer in women with African ancestry: a scoping review - Bianca Rossouw; Monica Araujo; Amanda Krause; Fiona Baine-Savanhu (Familial Cancer, 2026)
This scoping review explored genetic variants associated with hereditary ovarian cancer in women of African ancestry. Around 20% of ovarian cancers are hereditary, with BRCA1 and BRCA2 variants accounting for 20–55% of these cases, while other implicated genes include BRIP1, ATM, RAD51C, RAD51D , and the Lynch syndrome genes. The genetic basis of ovarian cancer in women of African ancestry, however, remains poorly understood. Accurate diagnosis of hereditary cancer syndromes is crucial given their personal and familial implications, informing patient management, surveillance, and cascade testing for at-risk relatives. Eligible studies included women of African ancestry with confirmed primary ovarian, peritoneal, or fallopian tube cancer who underwent germline genetic testing for hereditary cancer syndromes. Studies based solely on somatic testing or genome-wide association approaches were excluded. A comprehensive search of PubMed, Scopus, Web of Science, Google Scholar, and ProQuest Dissertations and Theses Global was conducted. Two reviewers independently screened citations and extracted data using a standardized form, and results were summarised narratively and in tables according to JBI scoping review guidelines. Thirty studies were included, primarily involving African American and North African participants. Only four focused specifically on hereditary ovarian cancer; the remainder primarily examined breast cancer cohorts with some ovarian cancer cases. Across these studies, 75 pathogenic variants were identified in 110 families, with 92% in BRCA1 or BRCA2 . Research on hereditary ovarian cancer in women with African ancestry remains extremely limited, highlighting the urgent need for broader next-generation sequencing studies to inform clinical care.

Germline MLH1 c.-42 C > T is a likely pathogenic variant predisposing to a reduced-penetrance/modified Lynch syndrome phenotype featuring MLH1-methylated cancers - Daniel D. Buchanan; Rocio Alvarez; Khalid Mahmood; Mark Clendenning; Peter Georgeson; Romy Walker; Julia Como; Susan G. Preston; Sharelle Joseland; Kimia Mohammadsaeedi; Francesca Aguirre; Lisa Zhou; et al. (Familial Cancer, 2026)
The germline MLH1 c.-42 C > T (rs41285097) promoter variant has been identified in cases with MLH1-deficient colorectal or endometrial cancers but remains a variant of uncertain significance. Genetic testing identified two new MLH1 c.-42 C > T index cases from Australia and the USA. Clinicopathologic and molecular characterisation of tumour and non-neoplastic tissues was performed to investigate the potential mechanism of pathogenesis of this variant. The male Australian proband developed MLH1-deficient, BRAF p.V600 wildtype, CIMP-negative colon cancer at 61 years. MLH1 monoallelic methylation and a somatic pathogenic mutation, MLH1 c.1122_1126dup p.Asp376Valfs*27, were identified in his tumour. Droplet digital PCR (ddPCR) detected mosaic MLH1 methylation in normal colonic mucosa adjacent to the cancer (3.7%) with lower levels in blood (0.07%) and saliva (0.09%). The USA proband developed MLH1-deficient endometrial cancer at 38 years with MLH1 monoallelic methylation and loss-of-heterozygosity of the wildtype c.-42 C allele. No evidence of MLH1 methylation was found by ddPCR in normal tissues. MLH1 c.-42 C > T heterozygous relatives from both families had either no or extremely low levels of MLH1 methylation within blood or saliva. Allelic expression from MLH1 c.-42T was reduced to 70% relative to the wild-type allele in saliva from three heterozygotes. Three additional pedigrees were identified from the Colon Cancer Family Registry. Evaluation of combined multifactorial data from pooled informative index cases supports reclassification of this variant as “likely pathogenic” according to current ACMG/AMP mismatch repair gene-specific guidelines, though with likely reduced penetrance and/or modified phenotype. These findings highlight the clinical importance of identifying MLH1 c.-42 C > T to inform cancer risk management.

A history of the collaborative group of the Americas on inherited gastrointestinal cancer (CGA-IGC): 1995–2025 - Beth Dudley; Bruce M. Boman; Marc S. Greenblatt; Steven H. Erdman; Paul E. Wise; Randall E. Brand; Carol A. Burke; Jose G. Guillem; Michael J. Hall; Heather Hampel; Brandie Heald; Matthew F. Kalady; et al. (Familial Cancer, 2026)

Hearing preservation and restoration surgery in NF2-related schwannomatosis - Christopher G. Wood; Nathan Huey; Christine Carter; Nathaniel Truong; Fred G. II Barker; Scott R. Plotkin; D. Bradley Welling (Familial Cancer, 2026)

Exploration of familial genetic test result communication among Black women within an academic safety net hospital - Ruchi Aluwalia; Nadia Ali; Christine Stanislaw; Regina Leonis; Jade Jones; Jamie Paysour (Familial Cancer, 2026)

Delphi panel consensus on genetic testing for prostate cancer in Australia: Whom to test and how? - Kim Edmunds; Shiksha Arora; Sri Teppala; Paul Scuffham; David Fairbairn; Matthew J. Roberts; Lisa Horvath; David P. Smith; Haitham Tuffaha (Familial Cancer, 2026)
The purpose of this study was to estimate the consensus of Australian Health Professionals and/or Researchers (HP/Rs) and Consumers (patients/family/carers) (Cs) on international genetic testing recommendations. Modified Delphi Panel study with seven domains of interest. Fifty-five statements were devised for an online survey administered in REDCap. HP/Rs and Cs were recruited from professional networks and associations for participation in the study. Statements were rated using a Likert scale and analysed using descriptive statistics. Free text comments were allowed within each domain and analysed using thematic analysis. Thirty-six HP/Rs and 27 Cs participated. There was consensus on testing men with a family history of a high-risk hereditary gene; men with PCa and a family history of Hereditary Breast and Ovarian Cancer (HBOC) syndrome or Lynch syndrome; and men with metastatic PCa. There was consensus on testing BRCA2, BRCA1 and DNA MMR genes for men with metastatic PCa. Thematic analysis of HP/R comments revealed three main topics: the lack of information to make a decision, insufficient knowledge of genetic testing, and capacity to provide genetic testing and counselling. This is the first Australian study on genetic testing recommendations in PCa to inform who should be tested and how. Our study showed apparent deficits in knowledge and implementation, exacerbated by workforce issues around the provision of genetic counselling and testing. Future work should focus on evaluating these recommendations for implementation in Australian practice.

Development and pilot testing of AYA-RISE, a risk information and screening education intervention for adolescents and young adults with cancer risk syndromes - Junne Kamihara; Lauren Fisher; Jaclyn Schienda; Rebecca Vanderwall; Moran Snir; Guy Snir; Emilie Simmons; Andrew Khalaj; Evan Goler; Kayla V. Hamilton; Christopher C. Porter; Bojana Pencheva; et al. (Familial Cancer, 2026)

Hereditary renal cell carcinoma surveillance protocols: a review of the literature and proposed recommendations - Miguel Miranda; Catarina Ferreira; Miguel Fernandes; Filipe Lopes; André Ye; Ana Berta Sousa; Luís Costa; José Palma dos Reis; Tito Palmela Leitão (Familial Cancer, 2026)

Beyond 1100delC: distinct CHEK2 variants and unique cancer phenotypes in Northeast Brazil - Mariana Macambira Noronha; Pedro Robson Costa Passos; Valbert Oliveira Costa Filho; Thais Baccili Cury Megid; Fernanda Teresa de Lima; Danielle Calheiros Campelo Maia (Familial Cancer, 2026)

Japanese version of MICRA: introduction of the Shizuoka Cancer Center version - Hiroyuki Matsubayashi; Rina Harada; Eiko Ishihara; Yoshimi Kiyozumi; Satomi Higashigawa; Reiko Suzuki; David Cella; Jason Bredle; Lillian Savic; Paul Cella (Familial Cancer, 2026)

Description of six cases of melanoma in 512 patients with germline pathogenic variants in the TP53 gene - Elisabeth de A. C. Callegaro; Janina Pontes Pisani; Vanessa Monteleone; Maria Isabel Achatz (Familial Cancer, 2025)

Surgery in NF2-Schwannomatosis - Michel Kalamarides; Omar Pathmanaban; Matthieu Peyre; Andrew Thomas King (Familial Cancer, 2025)

Functional characterization of splice variants in hereditary breast and ovarian cancer susceptibility genes - Laura Rosado-Jiménez; Younes Mestre-Terkemani; Ángeles García-Aliaga; María D. Sarabia-Meseguer; Miguel Marín-Vera; José A. Macías-Cerrolaza; Pilar Sánchez-Henarejos; María R. García-Hernández; Marta Zafra-Poves; Beatriz C. Álvarez-Abril; Carmen B. López-Sánchez; María P. Moya-Martínez; et al. (Familial Cancer, 2025)

“It’s not any one thing, it’s always all of them, all at the same time”: quality of life in NF2-related schwannomatosis from patient and clinician perspectives - Sophia C. Carias; Frank D. Buono; Liesel Von Imhof; Sneha M. Yelamanchili; Hilary Chan; Kaleb H. Yohay; P. Leia Nghiemphu; Dusica Babovic-Vuksanovic; Scott R. Plotkin; Vanessa L. Merker (Familial Cancer, 2025)

“Choosing the main character”: healthcare professionals’ attitudes towards counselling patients about risk disclosure to relatives in the era of mainstream cancer genetic testing - Anna Öfverholm; Matilda Liljedahl; Agnes Elmberger; Per Karlsson; Anna Rosén (Familial Cancer, 2025)
Purpose This study explored healthcare professionals’ attitudes toward counselling patients on disclosing genetic cancer risk to relatives. Genetic counselling practices in Sweden are undergoing significant changes due to the increased use of genetic testing to assess hereditary risk and the implementation of mainstreamed testing in oncology care. These developments require an assessment of healthcare professionals’ perceived roles and responsibilities when working with patients with hereditary risk. Best practices need to be developed to effectively support risk disclosure, and subsequently risk management, to relatives. Method Data was collected through interviews with oncologists, gynaecologists, surgeons, clinical geneticists, and genetic counsellors, working in oncology care or at cancer genetics units. Data was analysed using reflective thematic analysis. Results The results are presented as four positions that healthcare professionals take, describing their attitudes towards counselling patients about risk disclosure to relatives. The position depends on whether they perceive healthcare or the patient as ultimately responsible for risk information reaching relatives, and whether their focus is on the patient or the at-risk relatives. There are several stakeholders involved, and hence 'characters in play'. Conclusion These results could serve as a basis for discussions on roles and responsibilities, while developing best practices regarding genetic counselling on hereditary cancer risk communication.

Pathogenic CDKN2A germline variants are rare in a cohort of unselected pancreatic cancer patients from Pakistan - Shumaila Arif; Noor Muhammad; Humaira Naeemi; Muhammad Usman Rashid (Familial Cancer, 2025)

Significant progress in hereditary gastrointestinal cancer research presented at the meeting of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) 10th meeting of InSiGHT, June 19th -22nd, 2024, Barcelona, Spain - H. F. A. Vasen (Familial Cancer, 2025)

Updated genetic testing in individuals with unexplained adenomatous polyposis and the diagnostic yield - Blake Rowell; Maegan E. Roberts; Pamela L. Brock; Julia Cooper; Rachel Pearlman; Matthew F. Kalady; Stacey Culp; Peter P. Stanich; Josie Baker (Familial Cancer, 2025)

The clinical spectrum of paediatric NF2- related schwannomatosis - Dorothy Halliday; Lucy Hanington (Familial Cancer, 2025)

Pancreatic cancer surveillance not recommended for familial adenomatous polyposis: a fine and gray risk analysis - Aleksander M. Bogdanski; Derk C.F. Klatte; Sobia I. Laghari; Alexandra M.J. Langers; Ananya Das; Barbara A.J. Bastiaansen; Bert A. Bonsing; Evelien Dekker; Jeanin E. Van Hooft; Jewel N. Samadder; Lodewijk A.A. Brosens; Lydia G. van der Geest; et al. (Familial Cancer, 2025)

Novel susceptibility genes for non-NF2-/LZTR1-/SMARCB1-related hereditary schwannomatosis - Clara Nogué; Lluis Salvador; Martin Hasselblatt; Barbara Rivera (Familial Cancer, 2025)

Molecular pathogenesis of the schwannomatosis genes and genetic testing strategies - Miriam J. Smith (Familial Cancer, 2025)
The three major schwannomatosis genes, NF2 , LZTR1 and SMARCB1 , are all located within approximately 9 megabases on chromosome 22 and cause three genetically distinct conditions with significant clinical phenotypic overlap. All forms of schwannomatosis predispose to the development of multiple schwannomas, but display differences in tumour location and long-term prognosis. In addition, high levels of mosaic disease can complicate clinical diagnosis. Genetic diagnosis can be critical for distinguishing between the three conditions to optimise clinical management, especially in cases of mosaic disease. This review summarises the distinctions between the clinical and genetic characteristics of each form of schwannomatosis and discusses the genetic analytic tools that are typically used to detect the variants found in these conditions.

Correction: Barriers and facilitators for medical oncologists in the further implementation of mainstream genetic testing in breast cancer care in the Netherlands - Chiem L de Jong; Gina Schijven; Ellen G Engelhardt; Agnes Jager; Margreet G. E. M. Ausems (Familial Cancer, 2025)

Patient and provider perspectives on how a mobile health application may address barriers to Lynch Syndrome care - Minh Do; Ashley Dafoe; Elizabeth K. Magnan; Jordan Clawson; Sheana Bull; Elizabeth P. Ryan; Michelle Springer; Talia Thompson; Swati G. Patel (Familial Cancer, 2025)

Hybrid neurofibroma/schwannoma in schwannomatosis—a diagnostically challenging benign peripheral nerve sheath tumour - Daniel Tippner; Maxim Anokhin; Jonas Scheffler; Fabio Hellmann; Stefan K. Plontke; Sandra Leisz; Anja Harder (Familial Cancer, 2025)
Hybrid neurofibroma/schwannoma tumors (HNS) represent a still underrecognized, yet clinically and diagnostically significant entity within the spectrum of schwannomatosis (SWN). While classical schwannomas have been well known for decades, HNS have only recently been described as a distinct histological pattern, composed of intermixed features typical of both schwannomas and neurofibromas. Differentiating HNS from pure neurofibroma (Nf) is critical, as misclassification may lead to an incorrect diagnosis of neurofibromatosis type 1 rather than SWN. The distinction of hybrid tumors (more precisely HNS) is especially important in SWN forms outside the neurofibromatosis type 2 (NF2) spectrum (NF2-SWN), where major diagnostic criteria are less well defined, making histological differentiation even more significant. At the molecular level, HNS frequently show alterations in the genes NF2 , LZTR1 , and SMARCB1 , often accompanied by characteristic losses of chromosome 22q. In addition, recurrent somatic mutations have been identified in genes such as ERBB2 , RET , KMT2A , and CTNNA3 . Methylation profiling classifies HNS within the schwannoma spectrum, supporting the hypothesis that they may be a morphological variant rather than a distinct entity, although this has not yet been conclusively confirmed. Histologically, HNS are characterized by a combination of mostly schwannoma-associated Antoni A patterns, collagen-rich neurofibroma-like areas, lymphocytic infiltrates, and, in some cases, plexiform growth. Given the diagnostic challenges, artificial intelligence-based image analysis, such as whole-slide imaging and radiomics, may offer valuable tools for more accurate identification of these tumors in the future. Initial studies in related fields have shown that such approaches can even surpass human-level accuracy. Nevertheless, an accurate histological and, if necessary, molecular evaluation remains essential—particularly for the correct classification as SWN and for ensuring appropriate genetic counseling to affected individuals.

The germline POLD1 c.1420 C > A (p.Leu474Ile) variant segregates with endometrial cancer, colorectal cancer and colonic polyps demonstrating hypermutation and defective POLD1 mutational signatures - Daniel D. Buchanan; Peter Georgeson; Romy Walker; Jihoon E. Joo; Mark Clendenning; Julia Como; Ryan O’Keeffe; Alysha Prisc; Yen Lin Chu; Mark A. Jenkins; Christophe Rosty; Ingrid M. Winship; et al. (Familial Cancer, 2025)

Endoscopic papillectomy for ampullary adenomas in familial adenomatous polyposis - C. Wehling; Y. Eckstein; A. Stenzinger; N. Ganion; T. Bruckner; P. Sauer; C. C. Zhang-Hagenlocher; M. Kantowski; R. Koschny (Familial Cancer, 2025)
Objectives of the study were to determine the success, complication and recurrence rate of endoscopic papillectomies in familial adenomatous polyposis (FAP) patients. Ampullary adenoma is frequent in familial adenomatous polyposis (FAP) patients. Endoscopic papillectomy is technically demanding for laterally spreading ampullary adenomas and bleeding, perforation and pancreatitis represent typical complications. 40 FAP patients undergoing endoscopic papillectomy were retrospectively analyzed. Data on periprocedural complications, histopathology, resection techniques and success were collected. Endoscopic papillectomy was performed in 21 male and 19 female patients. Mean adenoma size was 14 mm (8–40 mm). Additional mucosal resection was performed in 45%. Immediate and delayed bleeding occurred in 33% (n = 13) and 13% (n = 5), respectively. Bleeding was associated with male sex and pancreatic endoprosthesis. Endoscopically manageable perforation occurred in 2 patients. Acute pancreatitis occurred in 25% (n = 10) and was significantly associated with female sex. Histopathology revealed papillitis in 5% (n = 2), adenoma with low-grade dysplasia in 73% (n = 29), high-grade dysplasia in 13% (n = 5), and adenocarcinoma in 5% (n = 2). Cumulative recurrence-free resection was achieved in 94% (n = 33/35) after a mean of 1.4 procedures at a median follow-up of 591 days (range 15-2605). Endoscopic papillectomy shows a high clinical success in FAP patients even with laterally spreading adenoma. Adenoma recurrence can be successfully treated with a limited number of reinterventions.

The Tenth International Symposium on Hereditary Breast and Ovarian Cancer (Familial Cancer, 2025)

History and clinical epidemiology of NF2-related schwannomatosis - D. Gareth Evans; Jaishri O. Blakeley; Scott R. Plotkin (Familial Cancer, 2025)
NF2 -related schwanomatosis ( NF2- SWN) (previously Neurofibromatosis 2) as characterised by bilateral vestibular schwannomas (VS) was first described in 1822. However, due to the erroneous conflation of individuals with bilateral eighth nerve tumours with von Recklinghausen disease (currently Neurofibromatosis 1, NF1) in 1917 the literature was confusing for much of the 20th century. Even when the conditions were separated officially in 1987 (with separate localisation of the genes), NF2- SWN remained classified as a neurofibromatosis despite the tumours pathognomonic for NF1, neurofibromas, not being a feature of NF2-schwannomatosis. It is only in 2022 that NF2- SWN was correctly delineated as a schwannomatosis. The epidemiology of NF2- SWN has only been possible to delineate after the separation of NF2- SWN from the much more frequent nerve sheath predisposing tumour condition NF1. Two research groups have published on the birth prevalence and population prevalence of NF2- SWN in the UK and Finland. The most highly ascertained assessment of NF2- SWN cases from the Manchester region of England (population 4.8 million) gave a diagnostic prevalence of 1 in 50,500 and calculated birth prevalences of 1 in 27,956 respectively. However, an updated prevalence across England in 2024 (population 55 million) gave a prevalence of at least 1 in 58,000. NF2- SWN usually presents with bilateral vestibular schwannoma, but can present with meningioma or spinal tumour or ophthalmic features before a VS diagnosis or with a unilateral VS and other tumours and rarely with a unilateral VS alone. Molecular testing is now extremely helpful in confirming the diagnosis of mosaic (present in up to 50% of de novo cases) versus germline NF2 and distinguishing from other tumour predisposition conditions especially in childhood or cases with less common presentation. This chapter summarises the clinical epidemiology of NF2- SWN differentiating the condition from the overlapping non NF2- SWN.

Adenoma and carcinoma in the anal transitional zone following hand-sewn versus stapled ileal pouch-anal anastomosis in familial adenomatous polyposis - Jun Yong Han; Min Jung Kim; Sang Hui Moon; Young Jin Kim; Hyun Tae Lim; Jesung Park; Jae Hyun Park; Hyo Jun Kim; Ji Won Park; Seung-Bum Ryoo; Kyu Joo Park; Seung-Yong Jeong (Familial Cancer, 2025)
Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for familial adenomatous polyposis (FAP) in our institution. Stapled and hand-sewn IPAA differ in the amount of retained rectal mucosa, influencing both adenoma risk and functional outcomes. In this retrospective cohort study, we compared oncological and functional outcomes between the two techniques. Consecutive patients with FAP who underwent RPC with IPAA at Seoul National University Hospital between 1994 and 2022 were included. The ATZ adenoma and cancer occurrence, operative time, and anorectal functional outcomes were compared between hand-sewn and stapled anastomosis groups. The cumulative incidence risk of adenoma recurrence was compared using the log-rank test. 89 patients were analyzed: 32 underwent hand-sewn and 57 underwent stapled IPAA. Median follow-up was 100 months in the stapled group and 79 months in the hand-sewn group. Stapled IPAA was associated with shorter operative time (220.6 vs. 332.9 min, p < 0.001), lower diverting ileostomy rate (78.9% vs. 96.9%, p = 0.027), and lower Wexner incontinence scores (1.54 vs. 3.43, p = 0.009). Adenomas or carcinomas at the ATZ were identified in 29.2% of patients, with a higher 5-year adenoma recurrence in the stapled group (20.1% vs. 3.2%, p = 0.02). Most adenomas were successfully managed endoscopically, with no cancer progression in the stapled group. Two cancers occurred in the hand-sewn group during long-term follow-up. Stapled IPAA offers advantages in operative efficiency and anorectal function, with higher adenoma recurrence manageable under surveillance. These findings suggest stapled IPAA may be a reasonable surgical option for FAP when coupled with diligent follow-up.

Current surveillance in the Netherlands for urothelial carcinoma in lynch syndrome - B. H. J. Doornweerd; R. R. Kikkert; J. J. Koornstra; B. W. G. van Rhijn; E. J. van Gennep; A. M. J. Langers; I. J. de Jong; M. E. van Leerdam (Familial Cancer, 2025)
Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by a pathogenic germline variant in one of the mismatch repair (MMR) genes. There is a lack of evidence supporting surveillance for urothelial carcinoma (UC) in LS, however several surveillance strategies have been proposed in recent years. This has led to a variety of practices. This study reports on the current practice for UC surveillance in LS in the Netherlands. Individuals with LS from two university hospitals and a large comprehensive cancer center were selected. Data on UC surveillance and UC diagnoses were recorded. Cumulative incidence was calculated. Of 235 individuals with LS, 40% underwent UC surveillance. Individuals with a pathogenic MSH2 variant were under surveillance significantly more often than those with other pathogenic variants. Of the individuals who underwent surveillance 10% had annual testing and continued surveillance up until the last known follow up date. None of the surveillance tests led to a UC diagnosis. Of eight patients with UC, two were under active surveillance, but were diagnosed due to macroscopic hematuria after normal cytology results. Cumulative UC incidence was 9% at age 75. Currently, most individuals with LS in this cohort are not part of a surveillance program for UC. Cumulative UC risk is high, up to 9%, and none of the UC were detected by surveillance. Given the lack of evidence that a suitable surveillance test is available, we do not recommend surveillance for UC.

Implementation of risk-reducing surgery for HBOC under public insurance in Japan: a single-center experience - Hiroko Terui-Kohbata; Sayako Takahashi; Eriko Takamine; Mariko Komine; Maki Gau; Makiko Egawa; Yusuke Ebana; Tomoyuki Aruga; Kimio Wakana; Masayuki Yoshida (Familial Cancer, 2025)

Barriers and facilitators for medical oncologists in the further implementation of mainstream genetic testing in breast cancer care in the Netherlands - Chiem L de Jong; Gina Schijven; Ellen G Engelhardt; Agnes Jager; Margreet G. E. M. Ausems (Familial Cancer, 2025)
Only 67% of eligible patients with breast cancer currently undergo genetic testing. Mainstream genetic testing (i.e. healthcare professionals (HCPs) from outside the genetics field providing genetic counselling), also referred to asmainstreaming, leads to increased uptake of genetic testing. Unlike surgical oncologists, medical oncologists have not yet widely adopted mainstreaming. This study aims to identify barriers and facilitators for HCPs, in particular medical oncologists, in advancing the implementation of mainstreaming. Structured interviews were conducted with HCPs (predominantly medical oncologists) using the Constructive Technology Assessment (CTA) framework. Participants were recruited from all regions of the Netherlands, ensuring representation from academic medical centres, teaching hospitals and general hospitals. The interview data was analysed using thematic analysis. In this qualitative study, 12 medical oncologists, three nurse practitioners, three clinical geneticists, two clinical laboratory geneticists and one representative of a health insurer were interviewed. Lack of time and limited knowledge were the most commonly mentioned barriers, whilst effective cross-departmental collaboration and education were the most important facilitators. For medical oncologists specifically, financial compensation for the increased workload and the increasing importance of genetic testing for guiding therapy choices were found to be encouraging factors. This study identified several barriers and facilitators to mainstreaming being implemented by medical oncologists. Education to strengthen oncologists’ skills in discussing germline genetic testing may address knowledge gaps and time barriers. Alongside cross-departmental collaboration, these strategies could streamline genetic testing pathways. Further research should evaluate their implementation and effects on patient experience and equitable access.

Reclassification of an uncertain STK11 germline variant as likely pathogenic: a family study - Lorena Moreno; Miriam Cuatrecasas; Elia Grau; Míriam Potrony; Josep Oriola; Joan Anton Puig-Butillé; Teresa Ocaña; Teresa Ramón y Cajal; Francesc Balaguer; Sabela Carballal (Familial Cancer, 2025)

Cancer spectrum in Mexican patients with the CHEK2 p.(Leu236Pro) variant: a retrospective study - L. Leonardo Flores-Lagunes; Rosa María Alvarez-Gómez; Carolina Molina-Garay; Marco Jimenez-Olivares; Pablo Arturo Acosta-Mendez; Joaquin García-Solorio; Sebastián Prida-Riba; Karol Carillo-Sanchez; Elvia Cristina Mendoza-Caamal; Marcela Angélica De la Fuente-Hernández; Verónica Zoraya Fragoso-Ontiveros; Rodrigo Estefano Reyes Casarrubias; et al. (Familial Cancer, 2025)

Addressing unmet needs in Lynch syndrome: a patient-centered meeting to foster education, emotional support, and shared decision-making - Marina Antelo; Lucía Stach; Francesc Balaguer (Familial Cancer, 2025)

Navigating disclosure in new romantic partnerships as an adolescent or young adult with Li-Fraumeni syndrome - Camella J. Rising; Chloe O. Huelsnitz; Rowan Forbes Shepherd; Catherine Wilsnack; Patrick Boyd; Alix G. Sleight; Ashley S. Thompson; Sadie P. Hutson; Payal P. Khincha; Allison Werner-Lin (Familial Cancer, 2025)
Li-Fraumeni syndrome (LFS) is an early-onset cancer syndrome caused by pathogenic germline TP53 variants. Adolescents and young adults (AYAs) with LFS may have challenges navigating new romantic partnerships given the significant effects of LFS on multiple life domains that also affect partners (e.g., reproductive decision-making). Disclosing LFS-related information to new partners may be especially difficult given the uncertainty, complexity, and chronicity of LFS. This qualitative-descriptive study aimed to explore AYAs’ LFS disclosure decisions and experiences in new romantic partnerships. Participants were individuals with LFS aged 15–39 years at enrollment in a National Cancer Institute study. The analytic sample included 33 AYAs who completed at least one telephone interview. Greene’s disclosure decision-making model guided thematic analysis. Participants were mostly female (67%) and married/in a long-term relationship (58%), with mean age 29 years and ≥ 1 primary cancer (61%). Key factors in LFS disclosure decision-making included perceived relevancy to partners (e.g., future children’s genetic risk), partner traits (e.g., trustworthiness), and relationship quality (e.g., closeness). AYAs described LFS disclosures in new partnerships as a process. Disclosing LFS diagnosis often occurred early to fulfill a sense of moral obligation and emotionally self-protect from future rejection, while subsequent LFS disclosures depended on relationship quality and the topic’s emotional valence or complexity. Partners often earned AYAs’ trust by demonstrating a willingness to learn about and try to understand LFS. Clinicians and LFS communities could support AYAs by providing opportunities to discuss, normalize, and ameliorate challenges with LFS disclosures in new romantic partnerships (e.g., peer support groups, psychotherapy).

Comparative insight: hereditary colorectal cancer registries in Iran, Singapore, and South Africa - Ladan Goshayeshi; Ernest Wencong Eu; Raj Ramesar; Paul Goldberg; Yu Bin Tan; Ursula Algar; Rutharra Ghayadthri Manisekaran; Shao-Tzu Li; Rebecca Caeser; Adam Boutall; Lena Goshayeshi; Kevin J. Monahan; et al. (Familial Cancer, 2025)

Surgical management of the colorectum in FAP: tailored approaches for optimal outcomes - A. Sinha; J. G. Karstensen; D. Liska (Familial Cancer, 2025)
Familial adenomatous polyposis (FAP) is an inherited condition that predisposes individuals to colorectal cancer without preventive treatment. Surgical management typically involves restorative proctocolectomy with an ileal pouch anal anastomosis or colectomy with ileorectal anastomosis. Complete removal of the large intestine and rectum with a permanent stoma may also be required in selected cases. This narrative review highlights decision-making in FAP regarding the timing, extent, and modality of large bowel surgery. Key considerations include the extent of polyps, cancer risk in the remaining rectum, and associated extra-colonic manifestations like desmoid disease. The timing of surgery and the extent of bowel removal are critical factors requiring a personalized approach that considers patient preferences and clinical factors. Regardless of the chosen strategy, continued surveillance is essential to monitor disease progression.

A novel insertion/deletion in APC promotor 1B is associated with both gastric and colon polyposis - Frankie Fann; Marcy Richardson; Douglas Riegert-Johnson; Colin C. Young; Brittany F. Sears (Familial Cancer, 2025)

Response to letter of the editor ‘Screening for pancreatic cancer in high-risk individuals using MRI: optimization of scan techniques to detect small lesions’ - Bas Boekestijn; Martin N. Wasser (Familial Cancer, 2025)

Reliability and validity of the multidimensional impact of cancer risk assessment (MICRA) questionnaire: Japanese version - Tomoko Watanabe; Kaori Kimura; Minako Kakimoto; Yumie Hiraoka; Manami Matsukawa; Hiroko Nagahashi; Saki Horiguchi; Miwa Toshima; Chikako Tomozawa; Miki Aitani; Takeshi Kuwata; Teruhiko Yoshida; et al. (Familial Cancer, 2025)
This study aimed to develop and validate a Multidimensional Impact of Cancer Risk Assessment questionnaire–Japanese version (MICRA-J) as an assessment of the psychosocial impact of genetic testing. The MICRA was translated into Japanese using standardized translation procedures. The reliability and validity of the MICRA-J were evaluated in individuals who underwent BRCA1 / 2 testing for hereditary breast and ovarian cancer diagnosis. The 72 respondents included patients with BRCA1 / 2 pathogenic variants (n = 20), BRCA1 / 2 negative (n = 35), variants of uncertain significance (VUS, n = 6), participants with cascade testing positive (n = 7), and participants with cascade testing negative (n = 4). Total MICRA-J scores were positively correlated with Hospital Anxiety and Depression Scale (HADS) scores and negatively correlated with the 36-item short-form version 2 acute (SF-36v2 acute) scores ( P < 0.05). The MICRA-J showed good internal consistency coefficients (α > 0.70). Furthermore, high test–retest correlations were obtained when the 64 participants responded to the MICRA-J twice within a short period (Pearson’s correlation coefficient = 0.85). The MICRA-J Total score was higher in the groups with BRCA1 / 2 pathogenic variant carriers than in the BRCA1 / 2 negative group, whereas the HADS and SF36v2 acute did not differ significantly. These results suggest that the reliability and validity of the MICRA-J have been established. The MICRA-J, similar to the MICRA in other languages, is considered a useful tool to specifically measure the psychosocial impact of genetic testing.

CGA-IGC 2024 Abstracts (Familial Cancer, 2025)

SMARCB1-related schwannomatosis and other SMARCB1-associated phenotypes: clinical spectrum and molecular pathogenesis - Hildegard Kehrer-Sawatzki; David N. Cooper (Familial Cancer, 2025)
SMARCB1 is a core unit of the BAF chromatin remodelling complex and its functional impairment interferes with the self-renewal and pluripotency of stem cells, lineage commitment, cellular identity and differentiation. SMARCB1 is also an important tumour suppressor gene and somatic SMARCB1 pathogenic variants (PVs) have been detected in ~ 5% of all human cancers. Additionally, germline SMARCB1 PVs have been identified in patients with conditions as clinically diverse as Rhabdoid Tumour Predisposition Syndrome type 1 (RTPS1), schwannomatosis and neurodevelopmental disorders such as Coffin-Siris syndrome (CSS). RTPS1 is characterized by the occurrence of highly malignant atypical teratoid rhabdoid tumours (AT/RT) affecting mostly infants, whereas SMARCB1 -related schwannomatosis is generally diagnosed after the age of 30 and is characterized by benign schwannomas. Patients with germline SMARCB1 PVs and neurodevelopmental disorders do not usually develop SMARCB1 -deficient tumours but instead exhibit severe intellectual disability and congenital malformations. It is intriguing how germline SMARCB1 PVs can be responsible for these very different pathologies. However, a network of different factors has emerged that play important roles in this context. Thus, the tumour phenotype associated with germline SMARCB1 PVs is determined by the nature and location of the SMARCB1 mutation and the timing of SMARCB1 inactivation in specific progenitor cells. Biallelic complete loss of SMARCB1 function during a narrow time window of early embryonic development in neural crest cells is essential for AT/RT development. By contrast, hypomorphic SMARCB1 PVs during later developmental stages affecting more differentiated Schwann cell precursors give rise to schwannomas. However, the loss of the wild-type SMARCB1 allele is insufficient for schwannoma growth which appears to be dependent upon concomitant somatic NF2 PVs in patients with SMARCB1 -related schwannomatosis according to the four-hit/three-step model of tumorigenesis. In patients with neurodevelopmental disorders such as CSS, germline PVs would appear to cluster within the C-terminal SMARCB1 domain, interfering with the nucleosomal interactions of SMARCB1 but not with its tumour suppressor activity.

Parental perspectives on the use of tumor molecular profiling and germline genetic testing during their children's cancer treatment - Marcelo M. Sleiman; Muriel R. Statman; Mary Rose Yockel; Yelena P. Wu; Jada G. Hamilton; Wendy K. Kohlmann; Jennie Vagher; Soren Feola; Luke D. Maese; Jing Chen; Burton Appel; Casey J. Mehrhoff; et al. (Familial Cancer, 2025)

Rate of germline pathogenic sequence variants in cancer susceptibility genes in an Israeli pediatric and adolescent cancer cohort: a single institute experience - Dana Nahom; Zehavit Frenkel; Amos Toren; Eitan Friedman; Iris Kventsel (Familial Cancer, 2025)
Multi-cancer predisposition gene panel testing (MCPGT) enables simultaneous deep-coverage genotyping of multiple CPGs (cancer predisposing genes) and detects germline pathogenic sequence variants (PSVs). Reported PSV carrier rates among pediatric and adolescent cancer patients range from 8 to 17.6%, with variability attributed to ethnic background, the number of genes tested, cancer phenotypes, and patient selection criteria. This study aimed to assess the rate and spectrum of germline PSVs in consecutive pediatric and adolescent cancer patients treated at the Sheba Medical Center, a tertiary medical center. All cancer patients aged 0–18 years treated between 01.2021 and 12.2022 were offered MCPGT. Overall, 257 eligible cancer patients were treated during the study period, of whom 116 Israeli patients underwent MCGPT (Invitae, San Francisco, CA), with complete data available for 108. The range of malignancies included central nervous system (CNS) tumors (n = 45), solid tumors (n = 37), hematological malignancies (n = 14), and retinoblastoma (RB) (n = 12). PSVs were detected in 17/108—15.7% of patients, with the highest rates in patients with RB (7/12, 58.3%) and CNS tumors (6/45, 13.3%). A significant association was found between younger age at diagnosis and PSV carrier status (4.7 years in carriers vs. 9.3 years in non-carriers, p = 0.003). Fulfilling Jongmans' criteria was correlated with PSV detection. The study highlights the importance of genetic testing in children meeting specific clinical criteria, particularly those diagnosed with RB and CNS tumors. Further studies with larger, ethnically diverse cohorts are needed to validate these findings to expand the scientific basis for personalized care strategies.

Copy number and structural variant analyses of VHL gene using droplet digital PCR and targeted adaptive sampling long-read sequencing - Shota Kato; Hiroko Terui-Kohbata; Atsushi Kudo; Masafumi Seki; Junko Takita; Tomohiro Morio; Yoshiko Nakano; Motohiro Kato; Masayuki Yoshida; Masatoshi Takagi (Familial Cancer, 2025)

Experiences with risk-reducing mastectomy in Norwegian BRCA1/2 carriers without prior breast cancer - Hanne Kjensli Hyldebrandt; Astrid Tenden Stormorken; Valeria Vitelli; Amy Østertun Geirdal; Eli Marie Grindedal (Familial Cancer, 2025)
Background: BRCA1 and BRCA2 carriers without prior breast cancer have the option to undergo risk-reducing mastectomy (RRM). The aim of this study was to investigate factors associated with their decision, experiences with the process, and satisfaction with the procedure. Materials and methods: We distributed a cross-sectional survey to 425 women aged 25–70 with a pathogenic BRCA1/2 variant. The survey collected data on sociodemographic factors, family cancer history, reasons for choosing RRM or not, experiences with the decision-making process, support from healthcare, and surgery satisfaction. Multivariate logistic regression analysis identified factors associated with the decision to undergo RRM and satisfaction with having undergone surgery. Results: Of the 272 respondents, 190 (69.9%) had undergone RRM. Having children and being a BRCA1 carrier were both associated with higher probability of choosing RRM, with an OR of 3.5 ( p = 0.005 and p < 0.001 respectively). Among those who had undergone RRM, 78.9% (150/190) were satisfied with their decision and would choose the same procedure again. Feeling satisfied with support from the health care system gave an OR of 5.5 for being satisfied with having undergone RRM ( p < 0.01). Those who found the decision difficult had lower odds of being satisfied (OR 0.2, p = 0.02). Conclusion: Being a BRCA1 carrier and having children were strongly associated with choosing RRM. Most participants felt relieved after RRM, were satisfied with their decision, and would choose the surgery again. Support from healthcare providers during decision-making was linked to higher satisfaction with having undergone surgery while those who struggled with the decision reported lower satisfaction.

MLH1 c.27G>A (p.Arg9=) is a synonymous likely/pathogenic variant underlying variably mosaic constitutional MLH1 methylation in Lynch syndrome - Rocio Alvarez; Paula Climent-Cantó; GiWon Shin; Francesca Paola Aguirre; Lisa Zhou; Dennis J. Hazelett; Brent K. Larson; Covadonga Vara; Gabriel Capellá; Víctor Lorca Castellanos; Pilar Garre Rubio; Françoise Desseigne; et al. (Familial Cancer, 2025)

Gastric-type endocervical adenocarcinoma in situ as the presenting feature in a mosaic STK11 pathogenic variant carrier with a Peutz-Jeghers syndrome child - Anqi Jiang; Yingfei Ye; Haowen Tan; Xiang Tao; Fenghua Ma; Hui Wang; Congjian Xu; Yu Kang (Familial Cancer, 2025)

Completeness of colorectal cancer registration in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register - Lars Joachim Lindberg; Inge Bernstein; Henrik Møller; Lone Sunde; Christina Therkildsen (Familial Cancer, 2025)
The Danish Hereditary Non-Polyposis Colorectal Cancer Register (HNPCC-R) has formed the basis for many epidemiologic studies supporting risk stratification and both national and international guidelines on surveillance. However, the HNPCC-R is based on voluntary reporting and the completeness of registration is unknown. Hence, we aimed to assess the validity and completeness of the colorectal cancer (CRC) registrations in the HNPCC-R. We combined the registrations in the HNPCC-R with the registrations in the national Danish Cancer Registry (DCR), which is validated and based on mandatory reporting, and matched the cases from each register using a 13-step algorithm based on unique, national Central Population Registration number, date of diagnosis, location, and morphology thus identifying 9160 verified CRCs in 49,799 individuals. The overall agreement between the registers was 85%, and the completeness of the HNPCC-R was 95%. The DCR had the highest number of registrations before 1975, and the HNPCC-R had the highest number of registrations after 1985—especially more synchronous and metachronous cases. In conclusion, data from the HNPCC-R on CRC are valid and should be preferred for studies on CRC in families with a heritable increased risk of colorectal cancer—especially in Lynch syndrome, which is known for multiple CRCs, though a combination of both registers would secure the most optimal dataset.

Updates and controversies for desmoids in familial adenomatous polyposis - Rami James N. Aoun; Matthew F. Kalady (Familial Cancer, 2025)
Desmoids are rare non-cancerous fibrous growths with variable behavior ranging from slow indolent growth or even regression, to locally aggressive and progressive tumors that can cause significant morbidity or mortality. Approximately 10–15% of patients with familial adenomatous polyposis (FAP) develop desmoid disease, most commonly located in the abdomen, on the abdominal wall, or in limbs. The majority of desmoids in FAP occur after abdominal surgery. Management is quite challenging and employing a multidisciplinary team at a specialized center is important for success. New treatment modalities have emerged, including tyrosine kinase inhibitors, γ-secretase inhibitors, and ablation techniques, complementing the existing repertoire of therapies such as NSAIDs, anti-hormonal therapy, chemotherapy, radiotherapy, and surgical interventions. Surgery remains the treatment of choice for easily resectable abdominal wall desmoids and intra-abdominal desmoids that cause intractable symptoms, or progressive disease despite alternate therapies, or complications from the invasion of nearby organs. When considering prophylactic colectomies in FAP patients, it’s essential to account for the desmoidogenic potential of surgical interventions, especially in high-risk individuals with a positive family history of desmoids, presence of extracolonic manifestations and carriers of certain genotypes. Given the rarity of the disease and the variability in both anatomical presentation and clinical course, desmoids should be managed by a multidisciplinary team capable of coordinating patient specific care and optimizing treatment options.

A coordinated multidisciplinary model of care is needed for child and family centered care in pediatric genetic cancer risk services: a scoping review - Andrew M. Grant; Natalie Taylor; Jane Maguire; Sharon de Graves; Christina Signorelli; Noemi A. Fuentes-Bolanos; Katherine M. Tucker; Marilyn Cruickshank (Familial Cancer, 2025)
Cancer remains a leading cause of death in children/adolescents. Approximately 8–18% of children/adolescents with cancer have an underlying pediatric Genetic Cancer Risk (p-GCR). P-GCR clinics offer surveillance aimed at improving survival outcomes. Yet children/adolescents require more than surveillance protocols to support holistic health. A multidisciplinary model of care (MoC), including Advanced Practice Nurses (APN) is needed. Yet a MoC and formal description of the APN is lacking in p-GCR clinics. To explore existing evidence of holistic, multidisciplinary approaches to care for children/adolescents and families with a p-GCR; to identify how Advanced Practice Nurses (APN) contribute to care delivery in p-GCR services. A scoping review was conducted in three databases: MEDLINE (Ovid), Embase (Ovid) and CINAHL Complete. JBI methodology for conducting and reporting scoping reviews was used to search MEDLINE, Embase and CINAHL Complete. Gray and white literature was considered from 1991 to 2023. Thirty two studies met inclusion criteria. Thirteen aspects of a MoC in p-GCR were identified including: clinic scope, clinic locality, clinicians involved, care coordination, clinic activity, geography, centralisation of care, psychosocial aspects, shared decision making, education, referrals, transition to adult services and research. There were 10 APN roles described that supported the service/organisation and the delivery of holistic care to children/adolescents with a p-GCR. Using a systematic approach, this review identified how services provide care to children/adolescents with a p-GCR and the APN role in these services. A multidisciplinary MoC with dedicated care coordination can enable child and family centred care with a holistic healthcare approach.

Hereditary breast cancer beyond BRCA: clinicopathological characteristics and long-term outcomes - Kwinten Dejaegher; Ines Nevelsteen; Sileny Han; Jelle Verhoeven; Hans Wildiers; Kevin Punie (Familial Cancer, 2025)

Familial adenomatous polyposis: non-surgical management of large bowel disease: endoscopic and chemoprevention strategies - Maria Daca-Álvarez; Andrew Latchford; Maria Pellisé; Francesc Balaguer (Familial Cancer, 2025)
Familial adenomatous polyposis (FAP) is a hereditary disorder caused by constitutional pathogenic variants in the APC gene, leading to the development of up to hundreds of colorectal adenomas and a near-inevitable risk of colorectal cancer (CRC) if untreated. Traditional management relies on prophylactic colectomy, but advances in endoscopic techniques and chemoprevention offer alternative strategies to delay or even avoid surgery. This review explores the role of endoscopic surveillance, polypectomy strategies, and chemopreventive agents in FAP management, evaluating their efficacy, limitations, and the need for personalized approaches.

Redefining familial adenomatous polyposis: competition, cooperation, and the path to monoclonality - Sylvain Ferrandon; Matthew F. Kalady; Sanne M. van Neerven (Familial Cancer, 2025)
Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by germline mutations in the APC gene that result in the development of hundreds of premalignant adenomas throughout the colon and rectum. Prophylactic surgery remains the primary intervention strategy, as there are currently no pharmacological treatment options for FAP patients. Previous therapeutic approaches have predominantly focused on reducing polyp size rather than preventing their initiation, thereby missing a key opportunity for early intervention. Crucially, to effectively target the earliest stages of tumour development requires a deeper understanding of the molecular mechanisms underlying adenoma formation. In this review, we evaluate the latest models and methods employed to investigate the origin of FAP adenomas. We describe how mutant cells expand from their initial emergence within the intestinal epithelium and how they compete with normal cells within intestinal crypts. In addition, we discuss how multiple mutant crypts cooperate to collectively form polyclonal adenomas, and how these polyclonal lesions gradually transition towards monoclonality as adenomas progress towards colorectal cancer. Finally, we highlight how these insights inform the development of targeted cancer prevention strategies for individuals with FAP.

Strategic Plan of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC): A practical roadmap to move the hereditary gastrointestinal cancer field forward - Bryson W. Katona; Peter P. Stanich; Anu Chittenden; Michael J. Hall; Gregory E. Idos; Cathryn Koptiuch; Alicia Latham; Rachel Pearlman; Aparajita Singh; Elana Levinson; Beth Dudley (Familial Cancer, 2025)

Upper GI polyposis and cancer in FAP: diagnosis, surveillance and treatment - Arthur S. Aelvoet; Yusaku Shimamoto; Yoji Takeuchi; Evelien Dekker; Carol A. Burke; Sonia S. Kupfer; Gautam Mankaney (Familial Cancer, 2025)

Detection rates of multigene panel and exome testing in patients with previous negative BRCA1/2 results - Jewel L. Wasson; Trinity N. Sprague; Darcy L. Thull; Maureen May; Kathleen E. Vitale; Shenin A. Sanoba; Alexander N. Yatsenko; Daniel Bellissimo; Phuong L. Mai (Familial Cancer, 2025)

5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin - Anna P. Sokolenko; Aigul R. Venina; Alexandr A. Romanko; Evgenia V. Belogubova; Alexandr V. Sultanbayev; Vadim E. Askarov; Gulnara K. Mukhamediarova; Elvina Kh. Bakaeva; Maria V. Syomina; Tatiana Yu. Velyukhova; Elena V. Preobrazhenskaya; Alexandr V. Togo; et al. (Familial Cancer, 2025)

Pancreatic adenocarcinoma in a patient with a germline RB1 pathogenic variant - Riya Patel; Christos Fountzilas; Michael Horowitz; Emily Schultz; Katherine M. Clayback; Erik S. Knudsen; Agnieszka K. Witkiewicz; Kenan Onel (Familial Cancer, 2025)

Screening of biobank SNP-array genotyping data to detect Lynch syndrome predisposing MLH1 copy number variants - Kimmo Ala-Kulju; Olli Carpén; Maarit Lappalainen; Minja Pehrsson (Familial Cancer, 2025)
Efficient use of genetic biobank data in support of clinical care would enhance the adoption of personalized medicine. Identification of carriers of medically actionable variants that predispose to cancer enables intensified screening and follow-up to decrease disease risk. Pathogenic variants of the MLH1 gene cause Lynch syndrome with a significant risk of developing cancer. Here, we introduce a novel approach for the large-scale screening of biobank SNP-array-based genotyping data to analyze copy-number variants (CNVs). With the method developed, we analyzed the Helsinki Biobank cohort of 121 073 samples and identified 29 MLH1 exon 16 deletion ( MLH1 ∆Ex16) carriers, of which five (17%) had not been previously identified in healthcare. Our results demonstrate a high positive predictive value for the identification of MLH1 ∆Ex16 carriers from genotyping data. The cost-efficient method for detection of CNV carriers from large biobank genotyping cohorts described here facilitates intensified screening and follow-up aiming to cancer prevention.

Advancing care for Lynch syndrome patients in China: challenges and opportunities - Shirley V. Hodgson; Hans F. A. Vasen (Familial Cancer, 2025)

Colonoscopy findings in CDH1 carriers from a multicenter international study - Arjun Chatterjee; Robert Hüneburg; Qijun Yang; Shannon Morrison; Anna Bettzüge; Tim Marwitz; Stefan Aretz; Isabel Spier; Tim Ripperger; Silke Redler; Mykyta Kachanov; Alexander E. Volk; et al. (Familial Cancer, 2025)
Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004–12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9–41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort ( p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40–26.7%); 45–49 years, 52.4% (95% CI: 32.4–71.7%); ≥50 years, 52.6% (95% CI: 37.3–67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25–40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.

Evaluation of BRCA1/2 testing rates in epithelial ovarian cancer patients: lessons learned from real-world clinical data - Lieke Lanjouw; Claire J. H. Kramer; Arja ter Elst; Geertruida H. de Bock; Katja N. Gaarenstroom; Refika Yigit; Lieke P. V. Berger; Christi J. van Asperen; Sabrina Z. Commandeur-Jan; Dimas M. X. van der Hall; Mathilde Jalving; Marjolein J. Kagie; et al. (Familial Cancer, 2025)
Identification of somatic and germline BRCA1/2 pathogenic variants in epithelial ovarian cancer (EOC) patients is essential for determining poly-(ADP-ribose)-polymerase (PARP) inhibitor sensitivity and genetic predisposition. In the Netherlands, BRCA1/2 testing changed to a tumor-first approach to efficiently identify both somatic and germline pathogenic variants in all patients. Here, we performed an in-depth evaluation of the first four years of the tumor-first test-pathway. Data of consecutive series of patients diagnosed with EOC in two regions were obtained from the Netherlands Cancer Registry. Tumor and/or germline test data were retrieved from hospital databases. The primary outcome was the percentage of patients completing the BRCA1/2 test-pathway, defined as having a negative tumor test or a referral for a germline test in case of a positive tumor test or no tumor test. Factors associated with test-pathway completion were identified through multivariable logistic regression analysis. In total, 69.8% (757/1085) completed the test-pathway. This was 74.4% in the most recent year. Younger patients, patients diagnosed in year three or four, patients with high-grade serous/high-grade endometrioid carcinoma, advanced stage disease, middle or high socioeconomic status, and patients who underwent surgery or chemotherapy, were more likely to complete the test-pathway. We report inequalities in genetic testing access in EOC patients, which highlight the need for better guideline adherence, particularly in older patients, those with low socioeconomic status, low-grade histotypes, early-stage disease and those without surgery or chemotherapy. Additionally, timely testing of patients, and testing relatives if patients cannot be tested, are crucial to increase test uptake.

The clinicopathological features of breast cancer in Peutz-Jeghers syndrome: results from an international survey - Elizabeth Loehrer; Anja Wagner; Massiah Bahar; F. Rubab Ramzan; Anne Marie Jelsig; Anne Goverde; Monique van Leerdam; Susanne E. Korsse; Evelien Dekker; Manon C. W. Spaander; John Gásdal Karstensen; Veronica Zuber; et al. (Familial Cancer, 2025)
Background: Female patients with Peutz-Jeghers syndrome (PJS) have an increased risk of breast cancer (BrCa), and surveillance is recommended. However, clinicopathological features of their tumors and prognosis are lacking. To facilitate more precise future guideline development, we evaluated these data. Methods: We conducted an international survey for InSiGHT members to collect retrospective data on PJS patients with diagnosed breast cancer. Results: We received 23 responses, including three centers with data on BrCa patients. All reported BrCa patients were female. In total, the cohort comprised 27 patients with 34 BrCa (five bilateral synchronous, one bilateral metachronous, and one metachronous unilateral tumours). The median age at first cancer diagnosis was 45 years (range 26–67). Most cancers were ductal carcinoma, either invasive (13) or in situ (DCIS; 19). TNM staging for invasive cancer was available in thirteen cases, of which nine were T1N0M0. Among tumors with histological reports, 14/15 were oestrogen receptor positive, 8/15 were progesterone receptor positive, and 4/15 were HER2 positive. There were no triple negative breast cancers. Twenty-five patients had follow-up data, comprising 229 patient years. Eleven patients had died of any cause during follow-up. Survival at 5 years was 73%. Conclusion: Overall, breast cancers that occur in this PJS population seem to have favorable characteristics and prognosis. These data will help inform discussions about risk management in patients with PJS. Further research is needed to better understand lifetime risk, the optimal surveillance modality and its outcomes.

A series of reviews in familial cancer: genetic cancer risk in context variants of uncertain significance in MMR genes: which procedures should be followed? - Morghan C. Lucas; Thomas Keßler; Florentine Scharf; Verena Steinke-Lange; Barbara Klink; Andreas Laner; Elke Holinski-Feder (Familial Cancer, 2025)

Intestinal transplantation in Familial Adenomatous Polyposis - Emilio Canovai; Sarah Upponi; Irum Amin (Familial Cancer, 2025)
In patients with Familial Adenomatous Polyposis (FAP), large desmoid tumors can develop all over the body. However, the most frequent presentation is as large intra-abdominal masses, usually located in the mesentery of the small bowel. From there, they tend to grow and invade both the abdominal wall and/or the retroperitoneal structures. This can cause life-threatening complications such as recurrent abdominal sepsis with fistulation and damage to vital organs. In selected patients, the only option may be radical resection and replacement by intestinal transplantation (ITx). We aimed to review all the current literature on ITx for FAP-related desmoids and provide an update from the largest single-center experience (2007–2024). All patients undergoing ITx for FAP-related desmoid were included. Between 2007 and 2024, 166 ITx was performed in 158 patients at Addenbrooke’s Hospital, Cambridge, UK. Of these, 20 (12%) were for desmoid associated with FAP (10 modified multivisceral transplants, 8 isolated ITx and 2 liver-containing grafts). The five-year all-cause patient survival was 92%, median follow-up was 4.3 years. As the patients presented with very advanced disease, many technical challenges were faced such as: extensive ureteric involvement, abdominal wall fistulation, management of previously formed ileo-anal pouches and extra-abdominal recurrences. Graft selection was another evolving issue, as foregut resection- versus sparing techniques require careful preoperative risk stratification due to increased long-term cancer risk in FAP patients. For certain patients with advanced FAP/desmoid disease, ITx can allow for a radical resection with excellent survival and functional outcomes. However, there is a high degree of initial morbidity associated with the operation and patients should be appropriately counselled. Graft selection and degree of native organ resection requires a careful balanced discussion.

A review of APC somatic mosaicism and specific APC variants - I1307K and promotor variants - Shira Shur; Anna K. Sommer; Andrew Latchford; Isabel Spier; Lior H. Katz (Familial Cancer, 2025)
In the majority of patients with a classical Familial Adenomatous Polyposis (FAP) a pathogenic APC germline variant is identified; usually these are truncating variants in the coding region of APC. However, there are some special circumstances in which FAP is not the result of a pathogenic heterozygous germline variant in APC (mosaicism) and tspecific APC variants which do not cause FAP (I1307K and promotor variants). This paper will discuss these three conditions. APC somatic (postzygotic) mosaicism can be identified in up to 50% of unexplained adenomatous polyposis cases. The ability to identify APC postzygotic mosaicism depends on the the detection method (today usually next-generation sequencing) and also the tissue being analysed (investigation of multiple colorectal adenomas is more sensitive than leukocyte DNA). Identifying mosaicism has important implications in terms of an individual’s management and managing risk in family members. The I1307K variant in APC is prevalent among Ashkenazi Jews (AJ) but can also be found in Sephardi Jews and individuals of non-Jewish descent. While this variant does not cause polyposis, it increases the risk of colorectal cancer (CRC) by 1.68-fold in AJ individuals. However, the link between the I1307K variant and CRC risk in non-AJ populations, is less well-established. Furthermore, its potential impact on other types of cancer remains unclear. Consequently, the classification of this variant, along with appropriate screening and surveillance recommendations, remains a subject of ongoing debate among leading medical and genetic organizations. Variants in the APC promotor 1B region cause the relatively newly described condition of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). It is said to have an isolated gastric phenotype, with neither duodenal, large bowel nor extra-intestinal manifestations. There are many uncertainties regarding this condition, it’s penetrance and management. Lack of clinical data and poor understanding of the natural history of the condition remain significant barriers to developing guidelines to manage this condition.

Genetics, genomics and clinical features of adenomatous polyposis - Jihoon E. Joo; Julen Viana-Errasti; Daniel D. Buchanan; Laura Valle (Familial Cancer, 2025)
Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1 , MSH2 , MSH6 , PMS2 , MSH3 and probably MLH3 , and in the base excision repair genes MUTYH , NTHL1 and MBD4 . This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.

One hundred years of the St Mark’s hospital polyposis registry - Vicky Cuthill; Andy Latchford; Sue Clark (Familial Cancer, 2025)
The St Mark’s Hospital Polyposis Registry was founded in 1924, the first such unit in the world. This paper documents the development of the unit over the subsequent 100 years, which was inextricably linked to scientific and clinical advance in the field of polyposis syndromes.

Causes of DNA mismatch repair deficiency in sebaceous skin lesions demonstrating loss of MLH1 protein expression: constitutional over somatic MLH1 promoter methylation - Jihoon E. Joo; Khalid Mahmood; Mark Clendenning; Romy Walker; Peter Georgeson; Julia Como; Mark A. Jenkins; Michael D. Walsh; Ingrid M. Winship; Daniel D. Buchanan (Familial Cancer, 2025)
Approximately 30% of sebaceous skin lesions (or sebaceous neoplasia) demonstrate DNA mismatch repair (MMR)-deficiency. MMR-deficiency can be caused by Lynch syndrome, resulting from germline pathogenic variants in the DNA MMR genes MLH1 , MSH2 , MSH6 and PMS2 , but other causes include somatic MLH1 gene promoter hypermethylation, constitutional MLH1 gene promoter hypermethylation ( MLH1 epimutation), or biallelic somatic MMR gene mutations. In colorectal (CRCs) and endometrial cancers (ECs), tumour MMR-deficiency showing loss of MLH1 and PMS2 protein expression (MLH1/PMS2-deficiency) is predominantly caused by somatic MLH1 hypermethylation, however, it is not clear if somatic MLH1 hypermethylation is a cause of MLH1/PMS2-deficiency in sebaceous neoplasia. This study investigated the causes of MLH1/PMS2-deficiency in 28 cases with sebaceous neoplasia. Germline pathogenic variants in MLH1 were identified in 11 of 28 cases. Of the remaining 17 non-Lynch syndrome cases, two (11.8%) were positive for MLH1 hypermethylation in blood-derived DNA (constitutional MLH1 epimutations). The corresponding sebaceous tissue of these two cases also showed MLH1 hypermethylation. None of the other eight cases with sufficient sebaceous tissue-derived DNA for testing showed somatic MLH1 hypermethylation. Multi-gene panel testing of sebaceous tissue and matched blood-derived DNA identified four cases with biallelic somatic MLH1 mutations as the cause of MLH1/PMS2-deficiency. No cause of MLH1/PMS2-deficiency could be identified in one case. This study demonstrates that biallelic somatic MLH1 mutations and constitutional MLH1 epimutations underlie MLH1/PMS2-deficiency in sebaceous neoplasms after excluding Lynch syndrome. Unlike CRCs and ECs, somatic MLH1 hypermethylation was not identified suggesting it is not a common cause of MLH1/PMS2-deficiency in sebaceous neoplasia.

Guidelines for Familial Adenomatous Polyposis (FAP): challenges in defining clinical management for a rare disease - Benjamin Zare; Kevin J. Monahan (Familial Cancer, 2025)
Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally. These recommendations reflect the diverse needs and capabilities of varying health systems worldwide, including thresholds for intervention and population health priorities. Whilst guidelines are closely aligned in many regards, there are areas of disparity. However, alongside discrepancies in guideline recommendations, common challenges also face professional bodies across the globe. Generation of a robust evidence-base in the environment of limited data is difficult in rare diseases such as FAP, underscored by the fact that expert consensus opinion underpins virtually all guidelines. The presence of a wide phenotypic spectrum in FAP and the other hereditary gastrointestinal polyposis syndromes, whilst now well recognised, further complicates the creation of universal recommendations. In this review we draw comparison between the various international guidelines for the management of FAP, using examples to focus on thematic areas of agreement and divergence. However, beyond this, we also wish to highlight the persisting evidence gaps in clinical management, and any areas of ongoing debate among clinicians, where we are yet to establish the optimal approach.

The patterns and spectrum of BRCA1 and BRCA2 mutations in Iranian breast and ovarian cancer patients - Shayan Forghani; Hamid Reza Mirzaee; Hamid Rezvani; Arman Forghani; Fatemeh Mahdavi Sabet; Ali Hojjat; Mona Malekzadeh; Atieh Akbari; Sanaz Tabarestani (Familial Cancer, 2025)

The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS): benefits for patients, families, and health care providers - Manon Engels; Katarzyna Urbanczyk; Jurriaan Hölzenspies; Claas Röhl; Nicoline Geverink; Nicoline Hoogerbrugge (Familial Cancer, 2025)
The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) established in 2017 and connecting more than 50 European expert centres improves access to diagnosis, treatment, and the provision of high-quality healthcare for patients with rare genetic tumour risk syndromes (hereditary cancer), no matter where they live in Europe.

Endometrial thickness among BRCA mutation carriers undergoing prophylactic oophorectomy - Michelle Jacobson; Adrianna Klejnotowska; Ping Sun; Steven A. Narod; Joanne Kotsopoulos (Familial Cancer, 2025)

Azacitidine and venetoclax for the treatment of AML arising from an underlying telomere biology disorder - Arjun Pandey; Talia Mancuso; Lea Velsher; James A. Kennedy (Familial Cancer, 2025)

Correction: The genetic landscape of Lynch syndrome in the Israeli population - Aasem Abu Shtaya; Sofia Naftaly Nathan; Inbal Kedar; Eitan Friedman; Elizabeth Half; Gabi Lidzbarsky; Gili Reznick Levi; Ido Laish; Lior Katz; Lily Bazak; Lilach Peled Peretz; Lina Basel Salmon; et al. (Familial Cancer, 2025)

The current status of care for families with Lynch syndrome in China - Baoshuai Liu; Shouyu Pan; Xian Hua Gao (Familial Cancer, 2025)

Non-serous ovarian cancer in PTEN Hamartoma Tumor Syndrome: additional evidence for increased risk - Ane J. Schei-Andersen; Vera M. Witjes; Janet R. Vos; Arjen R. Mensenkamp; Anne van Altena; Jolanda Schieving; Michiel Simons; Janneke H. M. Schuurs-Hoeijmakers; Muriel A. Adank; Liselotte P. van Hest; Yvette van Ierland; Mirjam de Jong; et al. (Familial Cancer, 2025)
Increased hereditary cancer risk is one of the hallmarks of PTEN Hamartoma Tumor Syndrome (PHTS) which is caused by a pathogenic germline variant in PTEN . Case reports and some cohort studies have described ovarian cancer (OC) in PHTS patients. Previously, we observed an enrichment of non-serous OC in PHTS compared to sporadic cases (3% vs 1%). However, ovarian cancer is currently not considered a PHTS-related cancer. The aim of this study was to describe five PHTS patients with a pathogenic germline variant in PTEN with non-serous OC. Three of the non-serous OCs were mucinous carcinomas (49, 51 and 52 years) and two were malignant germ cell tumors (8 and 15 years) and all were diagnosed before genetic testing and PHTS diagnosis. In addition to OC, the described patients developed other PHTS-related benign and malignant lesions. We provide further evidence that non-serous ovarian cancer, especially mucinous, endometrioid and malignant germ cell tumors should be further investigated as potential PHTS-related cancers.

Optimizing MRI sequences and apparent diffusion coefficient parameters for small pancreatic ductal adenocarcinoma detection - Naoko Mori (Familial Cancer, 2025)

Addressing uncertainty in hereditary colorectal cancer: the role of a regional expert multidisciplinary team meeting - Avani Varde; Terri McVeigh; Vicky Cuthill; Angela F. Brady; Bianca DeSouza; Andrew Latchford; Kevin J. Monahan (Familial Cancer, 2025)
There is frequent uncertainty in both the precise quantification of risk, and the application of clinical interventions, designed to mitigate increased heritable colorectal cancer (CRC) susceptibility. We evaluated the role of a collaborative specialist multidisciplinary team meeting (MDM) for familial and hereditary CRC, led by the St Mark’s Hospital Centre for Familial Intestinal Cancer specifically in supporting the clinical management of uncertainty. A retrospective thematic analysis of meeting outcomes from inception in June 2020 until March 2023 was performed. Descriptive statistics were employed to ascertain clinicopathological data, clinical queries and whether MDM recommendations were outside the scope of current guidelines. In total 260 cases were discussed from 13 regional institutions. A prior personal history of cancer was present in 215 (82.6%), and a family history of CRC in 107(41.2%) and non-CRC 27(10.4%) cases. In thematic analysis uncertainty related to indications for genetic testing was considered in 148 (56.9%) of cases, with unexplained mismatch repair deficiency (u-dMMR) in 78 (30%) of cases, and resolution of molecular interpretation in 61 (23.5%). Surveillance related queries represented 55 (21.1%), and mainstreaming 29 (11%) of cases. Management was recommended beyond the scope of existing guidelines in 64 (24.6%) cases. This regional hereditary CRC MDM provides clinicians with support in areas of uncertainty in diagnosis and clinical management, supporting clinical decision-making where evidence and clinical guidelines may be limited. This model could be replicated to support complexity in clinical care in other geographical regions or other health conditions.

Healthcare provider-mediated cascade testing of Lynch syndrome to at-risk family members: an interview study - Serene Ong; Zi Yang Chua; Jeanette Yuen; Jianbang Chiang; Zhang Zewen; Joanne Ngeow; Tamra Lysaght (Familial Cancer, 2025)

A novel likely pathogenic germline variant in CDKN1B in a patient with MEN4 and medullary thyroid cancer - Fernández Mercè; Queralt Asla; Francisco J. Illana; Fusté Victòria; Hernández-Losa Javier; Sesé Marta; Carmela Iglesias; Susan M. Webb; Anna Aulinas (Familial Cancer, 2025)

CHEK2-related breast cancer: real-world challenges - Luiza N. Weis; Brittany L. Bychkovsky; Adela Rodríguez Hernandez; Romualdo Barroso-Sousa; Renata L. Sandoval (Familial Cancer, 2025)

New RPS20 gene variant in colorectal cancer diagnosis: insight from a large series of patients - Julie Amiot; Lara Gubeljak; Agathe Fontaine; Denis Smith; Isabelle Mortemousque; Nathalie Parodi; Jacques Mauillon; Edwige Kasper; Stéphanie Baert-Desurmont; Julie Tinat; Claude Houdayer (Familial Cancer, 2025)

Identification of a germline deep intronic PTEN-deletion leading to exonization through whole genome and targeted RNA sequencing - Morgane Boedec; Camille Aucouturier; Mathias Cavaillé; Raphaël Leman; Laurent Castéra; Hélène Delhomelle; Nancy Uhrhammer; Virginie Bernard; Sophie Giraud; Eulalie Lasseaux; Natalie Jones; Marie Bidart; et al. (Familial Cancer, 2025)

Thirty-year compliance with a surveillance program for patients with familial adenomatous polyposis - Boris Cleret de Langavant; Jéremie H. Lefèvre; Julie Metras; Antoine Dardenne; Lauren V. O’Connell; Maxime Collard; Yann Parc (Familial Cancer, 2025)

Myelodysplastic syndrome with dual germline RUNX1 and DDX41 variants: a rare genetic predisposition case - Virginia Bove; Maria Noel Spangenberg; Carolina Ottati; Lucia Vázquez; Ana I. Catalán; Sofía Grille (Familial Cancer, 2025)

Case review of perivascular epithelioid cell tumor occurring in patients with Li-Fraumeni syndrome - Natsuno Abe; Fumito Yamazaki; Hanako Tsujikawa; Ryosuke Kasuga; Nobuhito Taniki; Hiroyuki Shimada (Familial Cancer, 2025)

Correction: Outcomes of retesting in patients with previously uninformative cancer genetics evaluations - Shenin A. Sanoba; Erika S. Koeppe; Michelle F. Jacobs; Elena M. Stoffel (Familial Cancer, 2025)

Progress report on multiple endocrine neoplasia type 1 - Reut Halperin; Amit Tirosh (Familial Cancer, 2025)
Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by a germline pathogenic variant in the MEN1 tumor suppressor gene. Patients with MEN1 have a high risk for primary hyperparathyroidism (PHPT) with a penetrance of nearly 100%, pituitary adenomas (PitAd) in 40% of patients, and neuroendocrine neoplasms (NEN) of the pancreas (40% of patients), duodenum, lung, and thymus. Increased MEN1-related mortality is mainly related to duodenal-pancreatic and thymic NEN. Management of PHPT differs from that of patients with sporadic disease, as the surgical approach in MEN1-related PHPT includes near-total or total parathyroidectomy because of multigland hyperplasia in most patients and the consequent high risk of recurrence. NEN management also differs from patients with sporadic disease due to multiple synchronous and metasynchronous neoplasms. In addition, the lifelong risk of developing NEN requires special considerations to avoid excessive surgeries and to minimize damage to the patient’s function and well-being. This progress report will outline current insights into surveillance and management of the major clinical manifestation of MEN1 syndrome in children and adults with MEN1 diagnosis. In addition, we will discuss MEN1-like clinical presentation with negative MEN1 -genetic workup and future clinical and research directions.

Correction: Benign tumors and non-melanoma skin cancers in patients with fanconi anemia - Aura Enache; Bia Sajjad; Burak Altintas; Neelam Giri; Lisa J. McReynolds; Edward W. Cowen (Familial Cancer, 2025)

The challenge of preventing gastric cancer in patients under surveillance for familial adenomatous polyposis - Hicham Bouchiba; Arthur S. Aelvoet; Nicole C. T. van Grieken; Lodewijk A. A. Brosens; Barbara A. J. Bastiaansen; Evelien Dekker (Familial Cancer, 2025)
Several extra-colonic manifestations, including duodenal polyposis and desmoid tumors, are well-described manifestations in familial adenomatous polyposis (FAP). More recently, an increase in gastric cancer diagnoses has been observed in FAP. This case series presents nine patients with FAP who were diagnosed with gastric cancer at our FAP expertise center, of whom eight were diagnosed between 2017 and 2023, while before 2017 the only diagnosis of gastric cancer was in 2001. Among the nine cases of gastric cancer, seven were located in the proximal stomach amidst carpeting fundic gland polyposis and two were located in the distal stomach. Despite ongoing advances in endoscopic technology, all patients were diagnosed during regular endoscopic surveillance, and six of the nine patients died within two years. We aim to raise awareness on gastric cancer risk in FAP patients and stress the urgent need of improved gastric surveillance strategies with timely detection of gastric cancer precursors.

Haplotype analysis detects MLH1 founder variant in Indian Lynch syndrome patient cohort - Harsh Sheth; Jyoti Sadhwani; Abhinav Jain; S. G. Thenral; Vedam Ramprasad; D. Timothy Bishop (Familial Cancer, 2025)

Bilateral familial retinoblastoma diagnosed via optical coherence tomography following a normal funduscopic exam - Mitchell T. Allphin; Aparna Ramasubramanian (Familial Cancer, 2025)

Recurrent paraneoplastic nephrotic syndrome; insights from a Lynch syndrome patient with multiple malignancies - Myrthe A. de Jong; Marije Slingerland; Lukas J. A. C. Hawinkels; Maartje Nielsen; Augustinus S. L. P. Crobach; Eveline S. M. de Jonge-Muller; Antonius J. Rabelink; Alexandra M. J. Langers (Familial Cancer, 2025)

Sarcomas arising in MEN1 patients: demonstrating LOH of the MEN1 locus and loss of menin expression - Rachel S. van Leeuwaarde; Thorvardur R. Halfdanarson; Shwetha M. Sudhakar; Ruud W. J. Meijers; Andrew L. Folpe; Lodewijk A. A. Brosens (Familial Cancer, 2025)

Cascade genetic testing in hereditary cancer: exploring the boundaries of the Italian legal framework - Liliana Varesco; Francesco Di Tano; Juri Monducci; Stefania Sciallero; Daniela Turchetti; Claudia Bighin; Giulia Buzzatti; Irene Giannubilo; Lucia Trevisan; Linda Battistuzzi (Familial Cancer, 2025)

Hereditary breast and ovarian cancer genetic testing in unselected patients: example of private supplementation of public healthcare service - Francesca Fiorentino; Giovanni Innella; Federica Balducci; Laura Marullo; Giulia Lanzoni; Sara Miccoli; Laura Cardarelli; Daniela Turchetti; Sergio Tempesta (Familial Cancer, 2025)

A family-based approach to cascade genetic testing in a pediatric cancer genetics clinic - Rida Haider; Lauren Desrosiers-Battu; Sarah Scollon; Pawel Stankiewicz; Philip J. Lupo; Sharon E. Plon (Familial Cancer, 2025)

BRCAIndica: a resource for ACMG/AMP classified BRCA1 and BRCA2 variants - Aastha Vatsyayan; R. I. Anu; Prerika Mathur; Divya Uchil; Ashish Joshi; Aradhana Dwivedi; Bhawna Sirohi; Aju Mathew; Dileep Damodaran; Soumya Surath Panda; Spoorthy Kolluri; Shaji K. Ayillath; et al. (Familial Cancer, 2025)

Prevalence of cardiometabolic outcomes in women who underwent salpingo-oophorectomy to prevent hereditary breast and ovarian cancer: a meta-analysis - Francisco Cezar Aquino de Moraes; Lucca Dal Moro; Maria Eduarda Cavalcanti Souza; Anna Luíza Soares de Oliveira Rodrigues; Vitor Kendi Tsuchiya Sano; Bárbara Ferraz Barbosa; Lucas Gama Pacheco; Daniel Ferreira Cunha; Otávio Luiz de Queiroz; Dilma do Socorro Moraes de Souza; Danielle Feio; Carlos Stecca; et al. (Familial Cancer, 2025)

The genetic landscape of Lynch syndrome in the Israeli population - Aasem Abu Shtaya; Sofia Naftaly Nathan; Inbal Kedar; Eitan Friedman; Elizabeth Half; Gabi Lidzbarsky; Gili Reznick Levi; Ido Laish; Lior Katz; Lily Bazak; Lilach Peled Peretz; Lina Basel Salmon; et al. (Familial Cancer, 2025)
Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

Mainstreaming cancer genetics: feasibility of an advanced nurse practitioner-led service diagnosing Lynch syndrome from colorectal cancer in Ireland - Mechelle Loughrey; Lauren V. O’Connell; Lynda McSorley; Sean Martin; Ann Hanly; Des C. Winter; Ian M. Frayling; Kieran Sheahan; Rory Kennelly (Familial Cancer, 2025)

Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome - Heidi Hesselø Brinch; Anna Byrjalsen; Zuzana Lohse; Andreas Ørslev Rasmussen; John Gásdal Karstensen; Britta Schlott Kristiansen; Anne Marie Jelsig (Familial Cancer, 2025)
Serrated Polyposis Syndrome (SPS) is characterized by multiple and/or large serrated polyps in the colon and an increased risk of colorectal cancer (CRC). The etiology is largely unknown, but in a subset of patients with SPS, monoallelic pathogenic variants in RNF43 are detected. To date, however, the penetrance and phenotypic spectrum of patients carrying pathogenic variants (PV) in RNF43 are poorly described. We present eight patients both with and without serrated polyps from four unrelated families with likely pathogenic variants (LPV) in RNF43 and compare the results to current literature. The patients were referred to genetic counseling due to suspicion of hereditary cancer. They underwent genetic testing with custom NGS gene panels including RNF43 as part of a routine genetic work-up. Three LPVs, one multi-exon deletion and two nonsense variants, were detected in four families. Family I had a history of CRC and serrated polyps, but in the three other families (II‒IV) there was no history of CRC or serrated polyps. Colonoscopies in the probands of these families did not reveal any serrated polyps and/or CRC despite some of them being relatively old. Our findings suggest that the penetrance of RNF43 -related disease is much lower than previously thought, and raise questions about the connection between RNF43 and disease. The results highlight the complexity of genetic counseling in RNF43 positive families– particularly in families without polyposis. Further research is needed to elucidate the role of RNF43 in the risk of SPS and CRC.

Overlap syndrome of hereditary hemorrhagic telangiectasia and juvenile polyposis syndrome: ten years follow-up-case series and review of literature - Maria Laura Gonzalez; Carolina Vazquez; Maria J. Argüero; Juan P. Santino; Ana Braslavsky; Marcelo M. Serra (Familial Cancer, 2025)

MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence - Jinru Shia; Francisco Sanchez-Vega; Stanley Cho; Jie-Fu Chen; Chin-Tung Chen; Umesh Bhanot; Nil Urganci; Canan Firat; Peter Ntiamoah; Raymond A. Isidro; Amitabh Srivastava; Martin R. Weiser; et al. (Familial Cancer, 2024)

Use and feasibility of a Lynch Syndrome predictive model for inherited colorectal and endometrial cancer in a low-middle income country - Monica A. Bissmeyer; Angel Velarde; Ana S. Salazar; Abigail S. Zamorano (Familial Cancer, 2024)

A content analysis of parents’ reflections on pathogenic and uncertain pediatric oncology germline sequencing results - Katianne M. Howard Sharp; Mary Egan Clark; Niki Jurbergs; Annastasia Ouma; Lynn Harrison; Leslie Taylor; Kayla Hamilton; Rose B. McGee; Regina Nuccio; Stacy Hines-Dowell; Jami S. Gattuso; Michelle Pritchard; et al. (Familial Cancer, 2024)

Endoscopic screening for identification of signet ring cell gastric cancer foci in carriers of germline pathogenic variants in CDH1 - Lady Katherine Mejia Perez; Margaret O’Malley; Arjun Chatterjee; Ruishen Lyu; Qijun Yang; Michael W. Cruise; Lisa LaGuardia; David Liska; Carole Macaron; R. Matthew Walsh; Carol A. Burke (Familial Cancer, 2024)
To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.

Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome - Claire Freycon; Laura Palma; Crystal Budd; Frederic Coulombe; Leora Witkowski; Pierre Hainaut; William D. Foulkes; Catherine Goudie (Familial Cancer, 2024)

Asymptomatic Bloom syndrome diagnosed by chance in a patient with breast cancer - Evgeny Suspitsin; Darya Eliseyeva; Olga Chiryaeva; Evgeniya Belogubova; Svetlana Aleksakhina; Anna Sokolenko; Evgeny Imyanitov (Familial Cancer, 2024)

A dual biomarker in non-small cell lung cancer that predicts Li Fraumeni syndrome - Steven Sorscher (Familial Cancer, 2024)

Complications of colonoscopy surveillance of patients with Lynch syndrome – 33 years of follow up - Alexander Frank; Sophie Walton Bernstedt; Nigin Jamizadeh; Anna Forsberg; Charlotte Hedin; Johannes Blom; Ann-Sofie Backman (Familial Cancer, 2024)
Background and study aims: Lynch syndrome (LS) is a hereditary autosomal dominant condition, with an increased lifetime risk of developing malignancies including colorectal cancer (CRC). Current guidelines differ in recommended colonoscopy-surveillance intervals from 1 to 2 years. Although colonoscopy is considered a safe procedure, there are risks of severe adverse events (SAEs), such as perforation and bleeding, as well as adverse events (AEs), such as abdominal discomfort and post-colonoscopy gastrointestinal infections. Colonoscopy-related bleeding and perforation rates have been reported 0.17% and 0.11%, respectively. However, there are insufficient data regarding complications of colonoscopy-surveillance for LS patients. This study aims to investigate the risk of AEs among LS patients during colonoscopy in the Stockholm region. Patients and methods: This retrospective cohort study includes 351 LS patients undergoing endoscopic surveillance at the Karolinska University Hospital, August 1989 – April 2021. Data from endoscopic surveillance colonoscopies were extracted from patients’ medical records. Results: Of 1873 endoscopies in 351 LS patients, 12 complications (AEs) were documented within 30 days (0.64%) and with a total of 3 bleedings (SAEs, 0.16%). No perforations were identified. Conclusion: Colonoscopy surveillance for LS patients shows a comparatively low risk of AEs per-examination. Colonoscopy complications per-patient, including both SAEs and AEs, show a significantly higher risk. Colonoscopy complications only including SAEs, show a comparatively low risk. Understanding the lifetime risk of surveillance-related colonoscopy complications is important when designing targeted surveillance programmes.

Colonoscopic surveillance in Lynch syndrome: guidelines in perspective - Joaquín Castillo-Iturra; Ariadna Sánchez; Francesc Balaguer (Familial Cancer, 2024)
Lynch syndrome predisposes to a high risk of colorectal cancer and colonoscopy remains the primary preventive strategy. The prevention of colorectal cancer through colonoscopy relies on identifying and removing adenomas, the main precursor lesion. Nevertheless, colonoscopy is not an optimal strategy since post-colonoscopy colorectal cancer remains an important issue. In continuation of a 2021 journal review, the present article seeks to offer an updated perspective by examining relevant articles from the past 3 years. We place recent findings in the context of existing guidelines, with a specific focus on colonoscopy surveillance. Key aspects explored include colonoscopy quality standards, timing of initiation, and surveillance intervals. Our review provides a comprehensive analysis of adenoma-related insights in Lynch syndrome, delving into emerging technologies like virtual chromoendoscopy and artificial intelligence-assisted endoscopy. This review aims to contribute valuable insights into the topic of colonoscopy surveillance in Lynch syndrome.

Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections – a nationwide Danish cohort study with long-term follow-up - JG Karstensen; MD Wewer; S. Bülow; TVO Hansen; H. Højen; AM Jelsig; TP Kuhlmann; J. Burisch; HC Pommergaard (Familial Cancer, 2024)
Background: Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. Methods: All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. Results: Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4–8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. Conclusions: The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.

Report of the sixth meeting of the European Consortium ‘Care for CMMRD’ (C4CMMRD), Paris, France, November 16th 2022 - Léa Guerrini-Rousseau; Richard Gallon; Marta Pineda; Laurence Brugières; Stéphanie Baert-Desurmont; Carole Corsini; Volodia Dangouloff-Ros; Mark A. J. Gorris; Christine Haberler; Pauline Hoarau; Marjolijn C. Jongmans; Matthias Kloor; et al. (Familial Cancer, 2024)
Biallelic germline pathogenic variants in one of the four mismatch repair genes ( MSH2 , MSH6 , MLH1 and PMS2 ) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium “Care for CMMRD” (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects. Since its formation, the C4CMMRD consortium held meetings every 1–2 years (except in 2020 and 2021 due to the Covid 19 pandemic). The sixth C4CMMRD meeting was held in Paris in November 2022, and brought together 42 participants from nine countries involved in various fields of CMMRD healthcare. The aim was to update members on the latest results and developments from ongoing research, and to discuss and initiate new study proposals. As previously done for the fifth meeting of the C4CMMRD group, this report summarizes data presented at this meeting.

Correction: Clinician perspectives on policy approaches to genetic risk disclosure in families - Amicia Phillips; Danya F. Vears; Ine Van Hoyweghen; Pascal Borry (Familial Cancer, 2024)

Digital innovation for cancer risk assessment allows large-scale service redevelopment of regional cancer genetics service delivery - Alice Youngs; Andrea Forman; Marisa Elms; Kelly Kohut; Min Theik Hlaing; John Short; Helen Hanson; Katie Snape (Familial Cancer, 2024)
Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.

Risk-reducing salpingectomy with delayed oophorectomy to prevent ovarian cancer in women with an increased inherited risk: insights into an alternative strategy - TA Gootzen; MP Steenbeek; MHD van Bommel; J IntHout; CM Kets; RPMG Hermens; JA de Hullu (Familial Cancer, 2024)
Epithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.

Benign tumors and non-melanoma skin cancers in patients with Fanconi anemia - Aura Enache; Bia Sajjad; Burak Altintas; Neelam Giri; Lisa J. McReynolds; Edward W. Cowen (Familial Cancer, 2024)
Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study “Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study” (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11–64 and 0–56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA , followed by FANCC and FANCI . Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk.

Misclassification of a frequent variant from PMS2CL pseudogene as a PMS2 loss of function variant in Brazilian patients - Anthony Vladimir Campos Segura; Sara Iolanda Oliveira da Silva; Karina Miranda Santiago; Rafael Canfield Brianese; Dirce Maria Carraro; Giovana Tardin Torrezan (Familial Cancer, 2024)

Metastatic disease after removal of a renal cell carcinoma smaller than 3 cm in a patient with Birt-Hogg-Dubé syndrome, a case report - L. van Riel; C. M. Kets; L. P. van Hest; F. H. Menko; B. G. Boerrigter; S. M. Franken; R. M.F. Wolthuis; H. J. Dubbink; P. J. Zondervan; R. J.A. van Moorselaar; A. C. Houweling; I. van de Beek (Familial Cancer, 2024)

The 17th International Meeting on Psychosocial Aspects of Hereditary Cancer (IMPAHC) (Familial Cancer, 2024)

Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort - Lauri J. Sipilä; Mervi Aavikko; Janne Ravantti; Samantha Martin; Teijo Kuopio; Laura Lahtinen; FinnGen; Päivi Peltomäki; Jukka-Pekka Mecklin; Lauri A. Aaltonen; Toni T. Seppälä (Familial Cancer, 2024)
Some 50% of Finnish Lynch Syndrome (LS) cases are caused by a founder variant in MLH1 , in which the entire exon 16 has been lost due to an Alu-mediated recombination event. We piloted detecting the variant in FinnGen, a large genotyped cohort comprising approximately 10% of the current Finnish population, and validated the MLH1 founder variant status of identified individuals residing in the Central Finland Biobank catchment area. A consensus sequence flanking the deletion was identified in whole genome sequences of six LS individuals with the founder variant. Genotype data of 212,196 individuals was queried for regional matches to the consensus sequence. Enrichment of cancer and age at cancer onset was compared between matching and non-matching individuals. Variant status was validated for a subset of the identified individuals using a polymerase chain reaction assay. Allelic matches in a chosen target region was detected in 348 individuals, with 89 having a cancer diagnosis (Bonferroni-adjusted p-value = 1), 20 a familial cancer history (p-adj. < .001), with mean age of onset of cancer being 53.6 years (p-adj. = .002). Eighteen of potential variant carriers had been sampled by the Central Finland Biobank, of which four (22%) were validated as true variant carriers. The workflow we have employed identifies MLH1 exon 16 deletion variant carriers from population-wide SNP genotyping data. An alternative design will be sought to limit false positive findings. Large genotyped cohorts provide a potential resource for identification and prevention of hereditary cancer.

Somatic STK11 mosaicism in a Turkish patient with Peutz-Jeghers syndrome - Mustafa Yilmaz; Ogun Bebek; Yavuzhan Colak; Ayberk Türkyılmaz (Familial Cancer, 2024)

A retrospective cohort study of genetic referral and diagnosis of Birt-Hogg-Dubé Syndrome in patients with Trichodiscoma and Fibrofolliculoma skin lesions - Christina Shabet; Meera Kattapuram; Anna Burton; Renata Thoeny; Hailey Nielsen; Marie Louise Accardo; Emily H. Smith; Erika Koeppe; Tobias Else; Kelly B. Cha (Familial Cancer, 2024)

Optimizing the detection of hereditary predisposition in women with epithelial ovarian cancer: nationwide implementation of the Tumor-First workflow - Vera M. Witjes; Dorien M. A. Hermkens; Julie E. M. Swillens; Yvonne H. C. M. Smolders; Marian J. E. Mourits; Margreet G. E. M. Ausems; Joanne A. de Hullu; Marjolijn J. L. Ligtenberg; Nicoline Hoogerbrugge (Familial Cancer, 2024)
Genetic testing in patients with ovarian carcinoma (OC) is crucial, as around 10–15% of these women have a genetic predisposition to OC. Although guidelines have recommended universal germline testing for all patients with OC for a decade, implementation has proved challenging, thus resulting in low germline-testing rates (around 30–50%). Many new initiatives to improve genetic-testing rates have emerged, but most have been carried out at the local level, leading to differences in workflows within and between countries. We present an example of a nationwide implementation project that has successfully led to a uniform, high-quality genetic-testing workflow for women with OC. Nationwide multidisciplinary meetings generated consensus on the preferred workflow for OC genetic testing: the “Tumor-First” workflow. This workflow means starting by testing the tumor DNA for the presence of pathogenic variants in OC-risk genes, thus providing a prescreen to germline testing while yielding information on the effectiveness of treatment with PARP inhibitors. This new workflow efficiently stratifies genetic counseling and germline testing and reduces healthcare costs. Although challenging, the nationwide implementation of this workflow was successful, resulting in tumor-DNA testing rates exceeding 80%. In this article, we present our structured implementation approach, illustrate our implementation strategies—which were tailored to identified factors important to implementation—and share the lessons learned from the Tumor-First implementation project. This knowledge could facilitate the future implementation of workflows aimed at optimizing the recognition of hereditary cancers.

Novel telomerase reverse transcriptase gene mutation in a family with aplastic anaemia - M. Virijevic; I. Marjanovic; M. Andjelkovic; Lj Jakovic; D. Micic; A. Bogdanovic; S. Pavlovic (Familial Cancer, 2024)

A de novo germline pathogenic BRCA1 variant identified following an osteosarcoma pangenomic molecular analysis - Adrien Mouren; Albain Chansavang; Nadim Hamzaoui; Arunya Srikaran; Pierre Laurent-Puig; Laetitia Marisa; Sixtine De Percin; Audrey Lupo; Frédérique Larousserie; Hélène Blons; Anais L’Haridon; Nelly Burnichon; et al. (Familial Cancer, 2024)

Clinical and genetic characteristics of carriers of the TP53 c.541C > T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent - Johnathan Arnon; Aviad Zick; Myriam Maoz; Nada Salaymeh; Ahinoam Gugenheim; MazalTov Marouani; Eden Mor; Tamar Hamburger; Nagam Saadi; Anna Elia; Gael Ganz; Duha Fahham; et al. (Familial Cancer, 2024)
TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 ( TP53 ): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1–69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2–54)—19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.