Impact of hormonal contraception on endometrial histology in patients with Lynch syndrome, a retrospective pilot study - Marie Mawet; Clémence Evrevin; Antoine Dardenne; Frédéric Kridelka; Axelle Pintiaux; Nathalie Chabbert-Buffet (Familial Cancer, 2024)

Strategies for diagnosis and management of CMMRD in low-resource countries: report of a Tunisian family - Rania Abdelmaksoud-Dammak; Nihel Ammous-Boukhris; Dorra BenAyed-Guerfali; Yassine Gdoura; Imen Boujelben; Souhir Guidara; Slim Charfi; Wiem Boudabbous; Saloua Ammar; Wiem Rhaiem; Mohamed Zaher Boudawara; Hassen Kamoun; et al. (Familial Cancer, 2024)

A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America - Patricia Esperon; Florencia Neffa; Walter Pavicic; Florencia Spirandelli; Karin Alvarez; María José Mullins; Benedito Mauro Rossi; Rodrigo Felipe Góngora e Silva; Carlos Vaccaro; Francisco Lopéz-Köstner; Jorge Rugeles; Adriana Della Valle; et al. (Familial Cancer, 2024)

Clinical features of prostate cancer by polygenic risk score - Christina Spears; Menglin Xu; Abigail Shoben; Shawn Dason; Amanda Ewart Toland; Lindsey Byrne (Familial Cancer, 2024)
Genome-wide association studies have identified more than 290 single nucleotide variants (SNVs) associated with prostate cancer. These SNVs can be combined to generate a Polygenic Risk Score (PRS), which estimates an individual’s risk to develop prostate cancer. Identifying individuals at higher risk for prostate cancer using PRS could allow for personalized screening recommendations, improve current screening tools, and potentially result in improved survival rates, but more research is needed before incorporating them into clinical use. Our study aimed to investigate associations between PRS and clinical factors in affected individuals, including age of diagnosis, metastases, histology, International Society of Urological Pathology (ISUP) Grade Group (GG) and family history of prostate cancer, while taking into account germline genetic testing in known prostate cancer related genes. To evaluate the relationship between these clinical factors and PRS, a quantitative retrospective chart review of 250 individuals of European ancestry diagnosed with prostate cancer who received genetic counseling services at The Ohio State University’s Genitourinary Cancer Genetics Clinic and a 72-SNV PRS through Ambry Genetics, was performed. We found significant associations between higher PRS and younger age of diagnosis (p = 0.002), lower frequency of metastases (p = 0.006), and having a first-degree relative diagnosed with prostate cancer (p = 0.024). We did not observe significant associations between PRS and ISUP GG, histology or a having a second-degree relative with prostate cancer. These findings provide insights into features associated with higher PRS, but larger multi-ancestral studies using PRS that are informative across populations are needed to understand its clinical utility.

Understanding familial risk of pancreatic ductal adenocarcinoma - Raymond M. Paranal; Laura D. Wood; Alison P. Klein; Nicholas J. Roberts (Familial Cancer, 2024)

Pilot study of a decision aid on BRCA1/2 genetic testing among Orthodox Jewish women - Meghna S. Trivedi; Haley Manley; Haeseung Yi; Thomas Silverman; Wendy K. Chung; Paul S. Appelbaum; Rebecca Starck; Isaac Schecter; Rita Kukafka; Katherine D. Crew (Familial Cancer, 2024)

Evaluation of EGFR and COX pathway inhibition in human colon organoids of serrated polyposis and other hereditary cancer syndromes - Priyanka Kanth; Mark W. Hazel; John C. Schell; Jared Rutter; Ruoxin Yao; Alyssa P. Mills; Don A. Delker (Familial Cancer, 2024)
Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study ( MYC, FOSL1 , EGR1, IL33, LGR5 and FOXQ1 ) may be used to identify other new molecular targets for chemoprevention of SSLs.

Progress report: Peutz–Jeghers syndrome - Anne Marie Jelsig; John Gásdal Karstensen; Thomas V. Overeem Hansen (Familial Cancer, 2024)

In Memoriam: Steffen Bülow (1943–2023) - Hans F. A. Vasen (Familial Cancer, 2024)

Aberrant transcription caused by an intronic non-canonical CDH1 variant - Ahmed Bouras; Chloé Grand-Masson; Cedrick Lefol; Eric Ruano; Fabienne Prieur; Qing Wang (Familial Cancer, 2024)

High amount of fertility reducing tumors and procedures, but no evidence for premature ovarian failure in female Lynch syndrome patients - Sabine Biermann; Michael Knapp; Peter Wieacker; Stefan Aretz; Verena Steinke-Lange (Familial Cancer, 2024)
Lynch syndrome (LS; HNPCC) patients carry heterozygous pathogenic germline variants in mismatch repair (MMR) genes, which have also been shown to play an important role in meiosis. Therefore, it was hypothesized, that LS might be associated with a higher risk for premature ovarian failure (POF) or earlier menopause. Data on medical gynaecological history, cancer diagnoses and therapy were collected from 167 female LS patients and compared to a population-based control cohort. There was no difference between the age of menopause in patients compared to controls and no evidence for a higher risk of POF in LS patients. However, around one third (35%) of the probands have already had premenopausal cancer and mostly cancer-related treatment affecting fertility before the age of 45 years. Therefore, childbearing time might still be limited in these patients, especially due to the premenopausal cancer risk. LS patients should be informed in time about the elevated premenopausal cancer risks and the possible impact on family planning. This is particularly relevant since the average childbearing age has increased during the last decades.

In memoriam: Gloria Petersen, PhD (1950-2023) - Hans Vasen (Familial Cancer, 2024)

Twenty-five years of surveillance for familial and hereditary pancreatic ductal adenocarcinoma: Historical perspectives and introduction to the special issue - Hans FA Vasen; Marcia Irene Canto; Michael Goggins (Familial Cancer, 2024)
In the 1990s, as prevention became a central strategy in the battle against cancer and the molecular genetics revolution uncovered the genetic basis of numerous hereditary cancer syndromes, there were no options available for patients at increased risk of developing pancreatic cancer. When surveillance efforts for those at familial and hereditary risk of pancreatic cancer emerged in the late 1990s, it was uncertain if early detection was achievable. In this introduction to the special issue, we offer an overview of the history of surveillance for pancreatic cancer, including the first reports of familial pancreatic cancer in the medical literature, the initial results of surveillance in the United States and the initiation of surveillance programs for hereditary pancreatic cancer in the Netherlands. This special issue features a collection of 18 articles written by prominent experts in the field, focusing specifically on refining surveillance methodologies with the primary objective of improving care of high-risk individuals. Several reviews in this collection highlight improved survival rates associated with pancreas surveillance, underlying the potential of early detection and improved management in the continuing fight against pancreatic cancer.

Attitudes toward genetic testing, family planning and preimplantation genetic testing in families with a germline CDKN2A pathogenic variant - A. M. Onnekink; D. C.F. Klatte; J. E. van Hooft; S. H. van den Berg; S. M.S. van der Zwaan; R. van Doorn; S. C.H. Hinnen; T. P. Potjer; E. M.A. Bleiker; M. E. van Leerdam (Familial Cancer, 2024)
Individuals with a germline CDKN2A pathogenic variant (PV) have a highly increased life time risk of melanoma and pancreatic cancer. This cross-sectional study assessed the attitudes among toward genetic testing, family planning, and preimplantation genetic testing (PGT) in confirmed CDKN2A PV carriers and individuals with a 50% risk of the PV (at-risk carriers) using of a one-time questionnaire. A total of 537 individuals were screened for eligibility, of whom 208 of 366 (57%) confirmed carriers (56% female, median age 54 years [IQR 46–63]) and 39 of 171 (23%) at-risk carriers (59% female, median age of 26 years [IQR 22–32]) participated in the study. Primary motivations for genetic testing were to gain control over their personal and children’s cancer risk, as well as increasing cancer surveillance practices. In contrast, concerns about obtaining a mortgage and life insurance were frequently cited as reasons for postponing genetic testing. Family planning decisions remained largely unaffected in both confirmed and at-risk carriers; however, the majority of confirmed carriers were still unaware of their familial or personal cancer risk when starting a family. More than 60% of the participants were unfamiliar with PGT and only a minority (19% of confirmed carriers and 10% of at-risk carriers) would be open to considering PGT as a reproductive option. This study found different attitudes toward genetic testing, family planning, and PGT among individuals affected by the CDKN2A PV. Understanding these different attitudes can help clinicians to address the complexities surrounding these issues, especially for younger individuals facing difficult decisions about the timing of genetic testing, family planning, and the potential use of assisted reproductive options.

Review of the cost-effectiveness of surveillance for hereditary pancreatic cancer - Louise Wang; Rachel Levinson; Catherine Mezzacappa; Bryson W. Katona (Familial Cancer, 2024)
Individuals with hereditary pancreatic cancer risk include high risk individuals (HRIs) with germline genetic susceptibility to pancreatic cancer (PC) and/or a strong family history of PC. Previously, studies have shown that PC surveillance in HRIs can downstage PC diagnosis and extend survival leading to pancreatic surveillance being recommended for certain HRIs. However, the optimal surveillance strategy remains uncertain, including which modalities should be used for surveillance, how frequently should surveillance be performed, and which sub-groups of HRIs should undergo surveillance. Additionally, in the ideal world PC surveillance should also be cost-effective. Cost-effectiveness analysis is a valuable tool that can consider the costs, potential health benefits, and risks among various PC surveillance strategies. In this review, we summarize the cost-effectiveness of various PC surveillance strategies for HRIs for hereditary pancreatic cancer and provide potential avenues for future work in this field. Additionally, we include cost-effectiveness studies among individuals with new-onset diabetes (NoD), a high-risk group for sporadic PC, as a comparison. Graphical Abstract

The best linear unbiased prediction (BLUP) method as a tool to estimate the lifetime risk of pancreatic ductal adenocarcinoma in high-risk individuals with no known pathogenic germline variants - Cristina-Marianini-Rios; María E. Castillo Sanchez; Ana García García de Paredes; Mercedes Rodríguez; Emma Barreto; Jorge Villalón López; Raquel Fuentes; María Muñoz Beltrán; Alfonso Sanjuanbenito; Eduardo Lobo; Alejandra Caminoa; Ignacio Ruz-Caracuel; et al. (Familial Cancer, 2024)
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the Western world. The number of diagnosed cases and the mortality rate are almost equal as the majority of patients present with advanced disease at diagnosis. Between 4 and 10% of pancreatic cancer cases have an apparent hereditary background, known as hereditary pancreatic cancer (HPC) and familial pancreatic cancer (FPC), when the genetic basis is unknown. Surveillance of high-risk individuals (HRI) from these families by imaging aims to detect PDAC at an early stage to improve prognosis. However, the genetic basis is unknown in the majority of HRIs, with only around 10–13% of families carrying known pathogenic germline mutations. The aim of this study was to assess an individual’s genetic cancer risk based on sex and personal and family history of cancer. The Best Linear Unbiased Prediction (BLUP) methodology was used to estimate an individual’s predicted risk of developing cancer during their lifetime. The model uses different demographic factors in order to estimate heritability. A reliable estimation of heritability for pancreatic cancer of 0.27 on the liability scale, and 0.07 at the observed data scale as obtained, which is different from zero, indicating a polygenic inheritance pattern of PDAC. BLUP was able to correctly discriminate PDAC cases from healthy individuals and those with other cancer types. Thus, providing an additional tool to assess PDAC risk HRI with an assumed genetic predisposition in the absence of known pathogenic germline mutations.

The Spanish Familial Pancreatic Cancer Registry (PANGENFAM): a decade follow-up of individuals at high-risk for pancreatic cancer - Julie Earl; Raquel Fuentes; María E. Castillo Sanchez; Ana García García de Paredes; María Muñoz; Alfonso Sanjuanbenito; Eduardo Lobo; Alejandra Caminoa; Mercedes Rodríguez; Emma Barreto; Jorge Villalón López; Ignacio Ruz-Caracuel; et al. (Familial Cancer, 2024)
The Spanish Familial Pancreatic Cancer Registry (PANGENFAM) was established in 2009 and aims to characterize the genotype and phenotype of familial pancreatic cancer (FPC). Furthermore, an early detection screening program for pancreatic ductal adenocarcinoma (PDAC) is provided to healthy high-risk individuals from FPC and hereditary pancreatic cancer families (first-degree relatives). This article describes our experience over the last 10 years in high-risk screening. Hereditary and familial pancreatic cancer families were identified through the oncology and gastroenterology units. High-risk individuals underwent annual screening with endoscopic ultrasound (EUS) and magnetic resonance (MRI) from age 40 or 10 years younger than the youngest affected family member. Results: PANGENFAM has enrolled 290 individuals from 143 families, including 52 PDAC cases and 238 high-risk individuals. All high-risk individuals eligible for screening were offered to enter the surveillance program, with 143 currently participating. Pancreatic abnormalities were detected in 94 individuals (median age 53 years (29–83), with common findings including cystic lesions and inhomogeneous parenchyma. Imaging test concordance was 66%. Surgical intervention was performed in 4 high-risk individuals following highly suspicious lesions detected by imaging. PANGENFAM is a valuable resource for science innovation, such as biobanking, with clinical and imaging data available for analysis. For high-risk families, it may offer a potential for early diagnosis. Collaboration with other national and international registries is needed to increase our understanding of the disease biology and to standardize criteria for inclusion and follow-up, optimizing cost-effectiveness and efficacy.

Familial and hereditary pancreatic cancer in Japan - Hiroyuki Matsubayashi; Chigusa Morizane (Familial Cancer, 2024)

The response of pancreatic acinar cell carcinoma to platinum and olaparib therapy in a germline BRCA2 variant carrier: case report and literature review - Hiroyuki Matsubayashi; Akiko Todaka; Takahiro Tsushima; Yoshimi Kiyozumi; Rina Harada; Eiko Ishihara; Satomi Higashigawa; Nobuyuki Ohike; Hiroki Sakamoto; Junya Sato; Hirotoshi Ishiwatari; Teichi Sugiura; et al. (Familial Cancer, 2024)

Expanding access to genetic testing for pancreatic cancer - Nicolette Juliana Rodriguez; Sapna Syngal (Familial Cancer, 2024)

Screening for pancreatic cancer in high-risk individuals using MRI: optimization of scan techniques to detect small lesions - Bas Boekestijn; Shirin Feshtali; Hans Vasen; Monique E. van Leerdam; Bert A. Bonsing; J. Sven D. Mieog; Martin N. Wasser (Familial Cancer, 2024)
Pancreatic cancer has a dismal prognosis in the general population. However, early detection and treatment of disease in high-risk individuals can improve survival, as patients with localized disease and especially patients with lesions smaller than 10 mm show greatly improved 5-year survival rates. To achieve early detection through MRI surveillance programs, optimization of imaging is required. Advances in MRI technologies in both hardware and software over the years have enabled reliable detection of pancreatic cancer at a small size and early stage. Standardization of dedicated imaging protocols for the pancreas are still lacking. In this review we discuss state of the art scan techniques, sequences, reduction of artifacts and imaging strategies that enable early detection of lesions. Furthermore, we present the imaging features of small pancreatic cancers from a large cohort of high-risk individuals. Refinement of MRI techniques, increased scan quality and the use of artificial intelligence may further improve early detection and the prognosis of pancreatic cancer in a screening setting.

The role of biomarkers in the early detection of pancreatic cancer - Michael Goggins (Familial Cancer, 2024)

The odyssee from surveillance to the detection of pancreatic cancer, total pancreatectomy, and its impact on life. insights from a p16-Leiden pathogenic variant carrier - Amarensia Spruitenburg; Hans FA Vasen (Familial Cancer, 2024)

Surgical aspects related to hereditary pancreatic cancer - Elisabeth Maurer; Detlef K. Bartsch (Familial Cancer, 2024)
The goal of surveillance programs for individuals at risk (IAR) from familial pancreatic cancer (FPC) families or families with other inherited tumor syndromes predisposing to the development of pancreatic adenocarcinoma (PDAC), such as hereditary pancreatitis or Peutz-Jeghers syndrome, is the dectection and consecutive curative resection of early PDAC or even better its high-grade precursor lesions. Although the indication for surgery is quite established, the extent of surgery is not well defined due to the lack of evidence-based data. In addition, multiple factors have to be taken into account to determine an optimal personalized surgical strategy. This holds especially true since pancreatic surgery is associated with a relatively high morbidity and might impair the quality of life significantly. In this article the surgical aspects in the setting of hereditary PDAC are discussed.

Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer - Aleksander M. Bogdanski; Jeanin E. van Hooft; Bas Boekestijn; Bert A. Bonsing; Martin N. J. M. Wasser; Derk C. F. Klatte; Monique E. van Leerdam (Familial Cancer, 2024)
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.

Genetic and other risk factors for pancreatic ductal adenocarcinoma (PDAC) - Michelle F. Jacobs; Elena M. Stoffel (Familial Cancer, 2024)

The role of endoscopic ultrasound in the detection of pancreatic lesions in high-risk individuals - Kasper A. Overbeek; Djuna L. Cahen; Marco J. Bruno (Familial Cancer, 2024)
Individuals at high risk of developing pancreatic ductal adenocarcinoma are eligible for surveillance within research programs. These programs employ periodic imaging in the form of magnetic resonance imaging/magnetic resonance cholangiopancreatography or endoscopic ultrasound for the detection of early cancer or high-grade precursor lesions. This narrative review discusses the role of endoscopic ultrasound within these surveillance programs. It details its overall strengths and limitations, yield, burden on patients, and how it compares to magnetic resonance imaging. Finally, recommendations are given when and how to incorporate endoscopic ultrasound in the surveillance of high-risk individuals.

The Italian registry of families at risk for pancreatic cancer (IRFARPC): implementation and evolution of a national program for pancreatic cancer surveillance in high-risk individuals - Livia Archibugi; Fabio Casciani; Silvia Carrara; Erica Secchettin; Massimo Falconi; Gabriele Capurso; Salvatore Paiella (Familial Cancer, 2024)

Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population? - J.-Matthias Löhr; Daniel Öhlund; Emma Söreskog; Emil Andersson; Miroslav Vujasinovic; Niklas Zethraeus; Malin Sund (Familial Cancer, 2024)
Screening of the general population for cancer is a matter of primary prevention reducing the burden of disease. Whilst this is successful for several cancers including breast, colon and prostate, the situation to screen and hence prevent pancreatic cancer is different. The organ is not as accessible to simple physical exam or biological samples (fecal or blood test). Neither exists a blood test such as PSA that is cost-effective. Reviewing the evidence from screening risk groups for pancreatic cancer, one must conclude that there is no rational at present to screen the general population, for a lack of appropriate tests.

Familial pancreatic cancer: a long fruitful journey - Teresa A Brentnall (Familial Cancer, 2024)

Precursor lesions in familial and hereditary pancreatic cancer - Michael J. Pflüger; Lodewijk A.A. Brosens; Ralph H. Hruban (Familial Cancer, 2024)

Cascade genetic testing: an underutilized pathway to equitable cancer care? - Roni Nitecki Wilke; Erica M. Bednar; Sara Pirzadeh-Miller; Sayoni Lahiri; Isabel C. Scarinci; Charles A. Leath III; Melissa K. Frey; Karen H. Lu; J. Alejandro Rauh-Hain (Familial Cancer, 2024)

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes: disclosure of genetic test results to relatives - Michiel Vlaming; Margreet G. E. M. Ausems; Gina Schijven; Inge M. van Oort; C. Marleen Kets; Fenne L. Komdeur; Lizet E. van der Kolk; Rogier A. Oldenburg; Rolf H. Sijmons; Lambertus A. L. M. Kiemeney; Eveline M. A. Bleiker (Familial Cancer, 2024)
Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives’ medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden.

Psychosocial barriers and facilitators for cascade genetic testing in hereditary breast and ovarian cancer: a scoping review - Agani Afaya; Sung-Won Kim; Hyung Seok Park; Myong Cheol Lim; Mi Sook Jung; Eun Ji Nam; Ji Soo Park; Joon Jeong; Jai Min Ryu; JiSun Kim; Jihye Kim; Minkyoung Kim; et al. (Familial Cancer, 2024)

Cascade testing for hereditary cancer in Singapore: how population genomics help guide clinical policy - Rebecca Caeser; Jianbang Chiang; Ee Shien Tan; E Shyong Tai; Joanne Ngeow (Familial Cancer, 2024)

Editorial for familial cancer: cascade genetic testing - Maria Katapodi; Joanne Ngeow; Yuen Yie; Melissa Frey (Familial Cancer, 2024)

Clinician perspectives on policy approaches to genetic risk disclosure in families - Amicia Phillips; Danya F. Vears; Ine Van Hoyweghen; Pascal Borry (Familial Cancer, 2024)
Genomic sequencing has emerged as a powerful tool with significant implications for patients and their relatives, however, empirical evidence suggests that effective dissemination of risk information within families remains a challenge. Policy responses to address this issue vary across countries, with Belgium notably lacking specific regulations governing nondisclosure of genetic risk. In this study, we conducted semi-structured interviews with clinicians from Belgian clinical genetics centers to gain insight into their perspectives on policy approaches to the disclosure of genetic risk within families. Using real-world examples of legislation and court rulings from France, Australia, and the UK, we explored clinician viewpoints on the roles and responsibilities of both patients and clinicians in the family communication process. Clinicians expressed confusion regarding what was legally permissible regarding contacting at-risk relatives. While there was a consensus among participants that patients have a responsibility to inform their at-risk relatives, participants were hesitant to support the legal enforcement of this duty. Clinicians mostly recognized some responsibility to at-risk relatives, but the extent of this responsibility was a subject of division. Our findings highlight the need for a comprehensive policy that clarifies the roles and responsibilities of clinicians and patients to inform at-risk relatives. Furthermore, the study underscores the practical challenges clinicians face in supporting patients through the complex process of family communication, suggesting a need for additional resources and the exploration of alternative approaches to communication.

Challenges and opportunities for Lynch syndrome cascade testing in the United States - Lauren E Passero; Megan C Roberts (Familial Cancer, 2024)

Cascade genetic testing for hereditary cancer syndromes: a review of barriers and breakthroughs - Rachel Levine; Ryan M. Kahn; Luiza Perez; Jesse Brewer; Samantha Ratner; Xuan Li; Effi Yeoshoua; Melissa K. Frey (Familial Cancer, 2024)

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre - D. Gareth Evans; Kate Green; George J. Burghel; Claire Forde; Fiona Lalloo; Helene Schlecht; Emma R. Woodward (Familial Cancer, 2024)
In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/ ). We present time trends (1990–2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1 , BRCA2 , and the Lynch genes ( MLH1 , MSH2 , MSH6 and PMS2 ) . For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73–1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 ( p < 0.0001).

Cascade genetic counseling and testing in hereditary syndromes: inherited cardiovascular disease as a model: a narrative review - Laura A. Grutters; Imke Christiaans (Familial Cancer, 2024)
Inherited cardiovascular diseases cover the inherited cardiovascular disease familial hypercholesterolemia and inherited cardiac diseases, like inherited cardiomyopathies and inherited arrhythmia syndromes. Cascade genetic counseling and testing in inherited cardiovascular diseases have had three decades of academic attention. Inherited cardiovascular diseases affect around 1–2% of the population worldwide and cascade genetic counseling and testing are considered valuable since preventive measures and/or treatments are available. Cascade genetic counseling via a family-mediated approach leads to an uptake of genetic counseling and testing among at-risk relatives of around 40% one year after identification of the causal variant in the proband, with uptake remaining far from complete on the long-term. These findings align with uptake rates among relatives at-risk for other late onset medically actionable hereditary diseases, like hereditary cancer syndromes. Previous interventions to increase uptake have focused on optimizing the process of informing relatives through the proband and on contacting relatives directly. However, despite successful information dissemination to at-risk relatives, these approaches had little or no effect on uptake. The limited research into the barriers that impede at-risk relatives from seeking counseling has revealed knowledge, attitudinal, social and practical barriers but it remains unknown how these factors contribute to the decision-making process for seeking counseling in at-risk relatives. A significant effect on uptake of genetic testing has only been reached in the setting of familial hypercholesterolemia, where active information provision was accompanied by a reduction of health-system-related barriers. We propose that more research is needed on barriers -including health-system-related barriers- and how they hinder counseling and testing in at-risk relatives, so that uptake can be optimized by (adjusted) interventions.

Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention? - Lucia Trevisan; Lea Godino; Linda Battistuzzi; Giovanni Innella; Elena Luppi; Giulia Buzzatti; Viviana Gismondi; Eva Blondeaux; Luigina Ada Bonelli; Daniela Turchetti; Liliana Varesco (Familial Cancer, 2024)

CGA-IGC 2023 Abstracts (Familial Cancer, 2024)

Low prevalence of gastric intestinal metaplasia and Helicobacter pylori on surveillance upper endoscopy in Lynch syndrome - Marya Pulaski; Michaela Dungan; Marina Weber; Gillain Constantino; Bryson W. Katona (Familial Cancer, 2024)

Breast density in NF1 women: a retrospective study - R. De Santis; G. Cagnoli; B. Rinaldi; D. Consonni; Beatrice Conti; M. Eoli; A. Liguori; M. Cosentino; G. Carrafiello; O. Garrone; M. Giroda; C. Cesaretti; et al. (Familial Cancer, 2024)
Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by neurofibromin haploinsufficiency due to pathogenic variants in the NF1 gene. Tumor predisposition has long been associated with NF1, and an increased breast cancer (BC) incidence and reduced survival have been reported in recent years for women with NF1. As breast density is another known independent risk factor for BC, this study aims to evaluate the variability of breast density in patients with NF1 compared to the general population. Mammograms from 98 NF1 women affected by NF1, and enrolled onto our monocentric BC screening program, were compared with those from 300 healthy subjects to verify differences in breast density. Mammograms were independently reviewed and scored by a radiologist and using a Computer-Aided Detection (CAD) software. The comparison of breast density between NF1 patients and controls was performed through Chi-squared test and with multivariable ordinal logistic models adjusted for age, body mass index (BMI), number of pregnancies, and menopausal status.breast density was influenced by BMI and menopausal status in both NF1 patients and healthy subjects. No difference in breast density was observed between NF1 patients and the healthy female population, even after considering the potential confounding factors.Although NF1 and a highly fibroglandular breast are known risk factors of BC, in this study, NF1 patients were shown to have comparable breast density to healthy subjects. The presence of pathogenic variants in the NF1 gene does not influence the breast density value.

Li Fraumeni Syndrome predisposes to gastro-esophageal junction tumours - Douglas Tjandra; Alex Boussioutas (Familial Cancer, 2024)
Li-Fraumeni Syndrome (LFS), caused by germline pathogenic variants in TP53 , predisposes to a wide range of young-onset malignancies, particularly sarcoma, breast and brain cancer. More recently, an increased risk of gastric adenocarcinoma has been recognised, although uptake of surveillance upper endoscopy is unclear. Our retrospective review of 65 patients with LFS, of whom 53.8% had undergone endoscopy, identified four patients (6.2%) with gastro-esophageal junction (GEJ) adenocarcinomas. Two cases were found on asymptomatic screening and were early stage. No cases had family history of gastrointestinal malignancy. Reviewing genomic data from The Cancer Genome Atlas Program, 76.4% of sporadic esophageal adenocarcinomas harboured somatic TP53 pathogenic variants, compared with 39.9% of non-cardia gastric cancers. This similar pattern observed in germline and sporadic cases warrants further investigation. We propose that upper endoscopy be recommended to all patients with LFS, with a focus on appropriate surveillance of the GEJ.

Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family - James M. Chan; Mark Clendenning; Sharelle Joseland; Peter Georgeson; Khalid Mahmood; Jihoon E. Joo; Romy Walker; Julia Como; Susan Preston; Shuyi Marci Chai; Yen Lin Chu; Aaron L. Meyers; et al. (Familial Cancer, 2024)
Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1 , a gene associated with breast and ovarian cancer and RNF43 , a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998–2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1 :c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43 :c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO 2019 ) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Functional and phenotypic consequences of an unusual inversion in MSH2 - Dylan Pelletier; Abhijit Rath; Nelly Sabbaghian; Manuela Pelmus; Catherine Hudon; Karine Jacob; Leora Witowski; Avi Saskin; Christopher D. Heinen; William D. Foulkes (Familial Cancer, 2024)

Balancing the burden and benefits of colonoscopy in Lynch Syndrome - Finlay Macrae (Familial Cancer, 2023)

PREMM5 distinguishes sporadic from Lynch syndrome-associated MMR-deficient/MSI-high colorectal cancer - Renata L. Sandoval; Miki Horiguchi; Chinedu Ukaegbu; C. Sloane Furniss; Hajime Uno; Sapna Syngal; Matthew B. Yurgelun (Familial Cancer, 2023)

Combining clinical and molecular characterization of CDH1: a multidisciplinary approach to reclassification of a splicing variant - Corrine Fillman; Arravinth Anantharajah; Briana Marmelstein; Monica Dillon; Carolyn Horton; Candace Peterson; Joseph Lopez; Rashmi Tondon; Terra Brannan; Bryson W Katona (Familial Cancer, 2023)

Prevalence and genetic spectrum associated with hereditary colorectal cancer syndromes, the need to improve cancer risk awareness, and family cascade testing in Vietnam - Huu-Thinh Nguyen; Y-Thanh Lu; Duc-Huy Tran; Ba-Linh Tieu; Kien-Trung Le; Truong-Vinh Ngoc Pham; Thanh-Thuy Thi Do; Dinh-Kiet Truong; Hoa Giang; Hung-Sang Tang (Familial Cancer, 2023)

Germline whole genome sequencing in adults with multiple primary tumors - Yiming Wang; Qiliang Ding; Stephenie Prokopec; Kirsten M. Farncombe; Jeffrey Bruce; Selina Casalino; Jeanna McCuaig; Marta Szybowska; Kalene van Engelen; Jordan Lerner-Ellis; Trevor J. Pugh; Raymond H. Kim (Familial Cancer, 2023)

Mainstreamed genetic testing of breast cancer patients: experience from a single surgeon’s practice in a large US Academic Center - Teresa S. Chai; Kanhua Yin; Mackenzie Wooters; Kristen M. Shannon; Kevin S. Hughes (Familial Cancer, 2023)

Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study - Anne Marie Jelsig; Thomas van Overeem Hansen; Lene Bjerring Gede; Niels Qvist; Lise-Lotte Christensen; Charlotte Kvist Lautrup; Ken Ljungmann; Louise Torp Christensen; Karina Rønlund; Pernille Mathiesen Tørring; Birgitte Bertelsen; Lone Sunde; et al. (Familial Cancer, 2023)
Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A , however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4 . In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40 years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈ 95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A , SMAD4 , and more rarely PTEN . However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.

Willingness of individuals with Li-Fraumeni syndrome to participate in a cancer prevention trial: a survey study - Farina J. Struewe; Sarah Schott; Martina de Zwaan; Christian P. Kratz (Familial Cancer, 2023)

Cancer surveillance for transgender and gender diverse patients with Lynch syndrome: a practice resource of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer - Rachel Hodan; Linda Rodgers-Fouche; Anu Chittenden; Mev Dominguez-Valentin; James Ferriss; Lauren Gima; Ole-Petter R. Hamnvik; Gregory E. Idos; Kevin Kline; Diane R. Koeller; Jessica M. Long; Danielle McKenna; et al. (Familial Cancer, 2023)

Clinical and imaging modality factors impacting radiological interpretation of breast screening in young women with neurofibromatosis type 1 - Mathilda Wilding; Jane Fleming; Katrina Moore; Ashley Crook; Ranjani Reddy; Sarah Choi; Timothy E. Schlub; Michael Field; Lavvina Thiyagarajan; Jeff Thompson; Yemima Berman (Familial Cancer, 2023)

In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma - Anisse Chami; Thalía Rodrigues de Souza Zózimo; Thamiris Matias Alves; Carolina Guimarães Ramos Matosinho; Cleydson Santos; Marcela Mattos Simões; Walter Luiz Ribeiro Cabral; Bernardo Ferreira de Paula Ricardo; Agnaldo Lopes da Silva Filho; Maria Raquel Santos Carvalho; Letícia da Conceição Braga (Familial Cancer, 2023)

A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report - Romy Walker; Mark Clendenning; Jihoon E. Joo; Jessie Xue; Khalid Mahmood; Peter Georgeson; Julia Como; Sharelle Joseland; Susan G. Preston; James M. Chan; Mark A. Jenkins; Christophe Rosty; et al. (Familial Cancer, 2023)
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6 :c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation ( MSH6 :c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.

Reclassification of two germline DICER1 splicing variants leads to DICER1 syndrome diagnosis - Maria Apellaniz-Ruiz; Nelly Sabbaghian; Anne-Laure Chong; Leanne de Kock; Semra Cetinkaya; Elvan Bayramoğlu; Winand N. M. Dinjens; W. Glenn McCluggage; Anja Wagner; Aslihan Arasli Yilmaz; William D. Foulkes (Familial Cancer, 2023)
DICER1 syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in DICER1 cause this condition. Detecting a variant of uncertain significance in DICER1 or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15 years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in DICER1 . However, two potentially splicing variants were found, DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somatic DICER1 RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome and the characterization of the germline intronic variants were all applied to recently described DICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.

Colonoscopy surveillance in Lynch syndrome is burdensome and frequently delayed - Elsa L. S. A. van Liere; Imke L. Jacobs; Evelien Dekker; Maarten A. J. M. Jacobs; Nanne K. H. de Boer; Dewkoemar Ramsoekh (Familial Cancer, 2023)
Individuals with Lynch syndrome have an increased colorectal cancer risk, hence, biennial colonoscopy surveillance is recommended. We aimed to investigate patients’ perception and preferences regarding surveillance, and to further explore compliance behaviour. Individuals with Lynch syndrome received a validated survey evaluating experiences of their three most recent colonoscopies. Individuals were non-compliant to surveillance if the interval between colonoscopies differed ≥ 6 months from the recommended interval. In total, 197 of 291 (68%) invited individuals returned the survey. They mostly underwent colonoscopy biennially (99%), under mild sedation (79%) and with bowel preparation performed by Moviprep® (99%). Surveillance was perceived as impacting quality of life in 21%, and as moderately to extremely burdensome in 57%, particularly in those below age 40. To lower the burden, patients prioritised improvements in volume and taste of bowel preparation, laxation-related bowel movements, waiting times, and a more personal and respectful approach of endoscopic staff. Additionally, many individuals (60%) would favour less-invasive surveillance modalities such as biomarkers. In total, 28% of individuals had delayed colonoscopy surveillance, predominantly for patient-related reasons. An additional 10% considered quitting/postponing surveillance. Upon multivariable analysis, patient-related delay was associated with low and medium education, history of ≤ 4 colonoscopies and having no hospital recall-system. Colonoscopy surveillance in Lynch syndrome is often experienced as burdensome, and frequently delayed. We identified determinants of surveillance behaviour in this population, and present potential interventions to reduce the burden and non-compliance rates.

Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome - J. K. Stone; N. A. Mehta; H. Singh; W. El-Matary; C. N. Bernstein (Familial Cancer, 2023)

Unusual phenotypes in patients with a pathogenic germline variant in DICER1 - Kateryna Venger; Miriam Elbracht; Julia Carlens; Peter Deutz; Felix Zeppernick; Lisa Lassay; Christian Kratz; Martin Zenker; Jung Kim; Douglas R. Stewart; Ilse Wieland; Kris Ann P. Schultz; et al. (Familial Cancer, 2023)
Pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

Ninth International Symposium on Hereditary Breast and Ovarian Cancer (Familial Cancer, 2023)

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature - Ketty Hu-Heimgartner; Noémie Lang; Aurélie Ayme; Chang Ming; Jean‑Damien Combes; Victor N. Chappuis; Carla Vazquez; Alex Friedlaender; Aurélie Vuilleumier; Alexandre Bodmer; Valeria Viassolo; José L Sandoval; et al. (Familial Cancer, 2023)
BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (g BRCA ) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7–14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 g BRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4–4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

Perspectives on the implications of carrying putative pathogenic variants in the medulloblastoma predisposition genes ELP1 and GPR161 - Miriam J Smith; Emma R Woodward; D Gareth Evans (Familial Cancer, 2023)
Recent genetic sequencing studies in large series’ of predominantly childhood medulloblastoma have implicated loss-of-function, predominantly truncating, variants in the ELP1 and GPR161 genes in causation of the MB SHH subtype specifically. The latter association, along with a report of an index case with some features of Gorlin syndrome has led to speculation that GPR161 may also cause Gorlin syndrome. We show that these genes are associated with relatively low absolute risks of medulloblastoma from extrapolating lifetime risks in the general population and odds ratios from the population database gnomAD. The projected risks are around 1 in 270–430 for ELP1 and 1 in 1600–2500 for GPR161. These risks do not suggest the need for MRI screening in infants with ELP1 or GPR161 variants as this is not currently recommended for PTCH1 where the risks are equivalent or higher. We also screened 27 PTCH1/SUFU pathogenic variant-negative patients with Gorlin syndrome for GPR161 and found no suspicious variants. Given the population frequencies of 0.0962% for GPR161 and 0.0687% for ELP1 , neither of these genes can be a cause of Gorlin syndrome with an unexplained population frequency far lower at 0.0021%.

Hereditary acute myeloid leukemia associated with C-terminal CEBPA germline variants - Amye M. Harrigan; Amy M. Trottier (Familial Cancer, 2023)

Characteristics of familial pancreatic cancer families with additional colorectal carcinoma - Bettina Lehman; Elvira Matthäi; Norman Gercke; Ulrike W. Denzer; Jens Figiel; Timo Hess; Emily P. Slater; Detlef K. Bartsch (Familial Cancer, 2023)
Familial pancreatic cancer (FPC) is a rare hereditary tumor entity with broad phenotypic heterogeneity, including colorectal carcinoma (CRC) in some families. The underlying factors for this co-occurrence are still not well evaluated. FPC families in the National Case Collection of Familial Pancreatic Cancer with an additional occurrence of CRC were analyzed regarding the phenotype, genotype and recommendation for a clinical screening program. The total cohort of 272 FPC families included 30 (11%) families with at least one CRC case. The proportion of affected family members with PDAC was 16.1% (73/451) compared to 9.3% of family members with CRC (42/451, p < 0.01). Females were affected with PDAC in 49% (36/73) and CRC in 38% (16/42). The median age of PDAC was 63 compared to 66 years in CRC, whereas 8 (26.6%) of families had an early onset of PDAC and 2 (6.7%) of CRC. Seventeen families had 2 or more affected generations with PDAC and 6 families with CRC. Eleven (9.6%) of affected patients had both PDAC and CRC. Potentially causative germline mutations (2 ATM , 1 CDKN2a , 1 MLH1 , 1 PALB2 ) were detected in 5 of 18 (27.7%) analyzed cases. These findings provide a step forward to include the phenotypic and genotypic characteristics of FPC-CRC families for the genetic counseling and management of these families. Nevertheless, results need to be verified in a larger patient cohort beforehand.

Heritable methylation marks associated with prostate cancer risk - James G. Dowty; Chenglong Yu; Mahnaz Hosseinpour; Jihoon Eric Joo; Ee Ming Wong; Tu Nguyen-Dumont; Joseph Rosenbluh; Graham G. Giles; Roger L. Milne; Robert J. MacInnis; Pierre-Antoine Dugué; Melissa C. Southey (Familial Cancer, 2023)
DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array. We used these families to systematically search the genome for methylation marks with Mendelian patterns of inheritance, then we tested the 1,000 most heritable marks for association with prostate cancer risk. After correcting for multiple testing, 41 heritable methylation marks were associated with prostate cancer risk. Separate analyses, based on 869 incident cases and 869 controls from a prospective cohort study, showed that 9 of these marks near the metastable epiallele VTRNA2-1 were also nominally associated with aggressive prostate cancer risk in the population.

Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition - Timo A. Kumpula; Susanna Koivuluoma; Leila Soikkonen; Sandra Vorimo; Jukka Moilanen; Robert Winqvist; Tuomo Mantere; Outi Kuismin; Katri Pylkäs (Familial Cancer, 2023)
CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.

Pilot study of the prevalence of autoimmune disorders in Li-Fraumeni syndrome - Ixtaccihuatl H. Obregón; Kelvin C. de Andrade; Renee C. Bremer; Payal P. Khincha; Sharon A. Savage (Familial Cancer, 2023)

Two unique BAP1 pathogenic variants identified in the same family by panel cascade testing - Lindsey Byrne; Cana Ingalls; Aliya Ansari; Cassie Porteus; Talia R. Donenberg; Daniel A. Sussman; Colleen M. Cebulla; Mohamed H. Abdel-Rahman (Familial Cancer, 2023)

A PMS2 non-canonical splicing site variant leads to aberrant splicing in a patient suspected for lynch syndrome - Ahmed Bouras; Pierre Naibo; Clémentine Legrand; François Le Marc’hadour; Eric Ruano; Chloé Grand-Masson; Cedrick Lefol; Qing Wang (Familial Cancer, 2023)

A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions - Meera Kattapuram; Christina Shabet; Sarah Austin; Michelle F. Jacobs; Erika Koeppe; Emily H. Smith; Lori Lowe; Tobias Else; Kelly B. Cha (Familial Cancer, 2023)

2022 CGA-IGC Annual Meeting: The collaborative group of the Americas on Inherited Gastrointestinal Cancer November 11–13, 2022 (Familial Cancer, 2023)

Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review - Shahram Aziz; Hazel O’Sullivan; Kara Heelan; Afrina Alam; Terri P. McVeigh (Familial Cancer, 2023)
A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.

Laboratory variation in the grading of dysplasia of duodenal adenomas in familial adenomatous polyposis patients - E. Soons; P. D. Siersema; L. M. A. van Lierop; T. M. Bisseling; M. C. A. van Kouwen; I. D. Nagtegaal; R. S. van der Post; F. Atsma (Familial Cancer, 2023)
To prevent duodenal and ampullary cancer in familial adenomatous polyposis (FAP) patients, a diagnosis of high grade dysplasia (HGD) plays an important role in the clinical management. Previous research showed that FAP patients are both over- and undertreated after a misdiagnosis of HGD, indicating unwarranted variation. We aimed to investigate the laboratory variation in dysplasia grading of duodenal adenomas and explore possible explanations for this variation. We included data from all Dutch pathology laboratories between 1991 and 2020 by retrieving histology reports from upper endoscopy specimens of FAP patients from the Dutch nationwide pathology databank (PALGA). Laboratory variation was investigated by comparing standardized proportions of HGD. To describe the degree of variation between the laboratories a factor score was calculated. A funnel plot was used to identify outliers. A total of 3050 specimens from 25 laboratories were included in the final analyses. The mean observed HGD proportion was 9.4%. The top three HGD-diagnosing laboratories diagnosed HGD 3.9 times more often than the lowest three laboratories, even after correcting for case-mix. No outliers were identified. Moderate laboratory variation was found in HGD diagnoses of duodenal tissue of FAP patients after adjusting for case-mix. Despite the fact that no outliers were observed, there may well be room for quality improvement. Concentration of these patients in expertise centers may decrease variation. To further reduce unwarranted variation, we recommend (inter)national guidelines to become more uniform in their recommendations regarding duodenal tissue sampling and consequences of HGD diagnoses.

Next-generation universal hereditary cancer screening: implementation of an automated hereditary cancer screening program for patients with advanced cancer undergoing tumor sequencing in a large HMO - Trevor L. Hoffman; Hilary Kershberg; John Goff; Kimberly J. Holmquist; Reina Haque; Monica Alvarado (Familial Cancer, 2023)
Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing to identify patients with hereditary cancer and determine if this approach augmented existing genetic counseling approaches driven by personal/family history criteria. Regular automated searches of a centralized tumor DNA variant database were performed for ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 variants, and germline hereditary cancer gene panel testing was offered to patients with tumor variants who had never undergone germline testing. Patients completing germline testing due to their tumor DNA test results were considered part of the tumor DNA safety net. Patients previously completing germline testing via traditional genetic counseling and tumor DNA safety net were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (P/LP) variant, and whether NCCN criteria were met for hereditary cancer genetic testing. Germline P/LP variants were common in both groups. Patients who received germline testing through traditional genetic counseling were more likely to have cardinal hereditary tumors than the tumor DNA safety net group. Patients identified with hereditary cancer through traditional genetic counseling were more likely to meet NCCN personal/family history criteria for germline testing than the tumor DNA safety net group (99% versus 34%). A universal tumor DNA safety net screen is an important diagnostic strategy which augments traditional genetic counseling approaches based on personal/family history.

A need to tailor surveillance based on family history: describing a highly penetrant familial paraganglioma kindred with an SDHD pathogenic variant - Madeline Foley; Anu Sharma; Kinley Garfield; Luke Maese; Luke Buchmann; Julie Boyle; Wendy Kohlmann; Joanne Jeter; Samantha Greenberg (Familial Cancer, 2023)

Barriers to completion of cascade genetic testing: how can we improve the uptake of testing for hereditary breast and ovarian cancer syndrome? - Ryan Matthew Kahn; Muhammad Danyal Ahsan; Eloise Chapman-Davis; Kevin Holcomb; Roni Nitecki; Jose Alejandro Rauh-Hain; Rana Khan Fowlkes; Francesca Tubito; Maira Pires; Paul J Christos; Kaitlyn Tkachuk; Hannah Krinsky; et al. (Familial Cancer, 2023)

Determinants of adherence to recommendations on physical activity, red and processed meat intake, and body weight among lynch syndrome patients - M Hoedjes; A Vrieling; L de Brauwer; A Visser; E Gómez García; N Hoogerbrugge; E Kampman (Familial Cancer, 2023)
This study aimed to identify determinants of adherence to lifestyle and body weight recommendations for cancer prevention among Lynch Syndrome (LS) patients. Cross-sectional baseline data of LS patients participating in the Lifestyle & Lynch (LiLy) study was used to assess determinants of adherence to the World Cancer Research Fund cancer prevention recommendations on body weight, physical activity, and red and processed meat intake. Adherence and potential determinants of adherence were assessed using questionnaires. Multivariable logistic regression analyses were conducted to identify determinants of adherence. Of the 211 participants, 50.2% adhered to the body weight recommendation, 78.7% adhered to the physical activity recommendation, and 33.6% adhered to the red and processed meat recommendation. Being younger and having a higher level of education were associated with adherence to the recommendation on body weight. Having knowledge about the recommendation was associated with adherence to the recommendations on physical activity and red and processed meat. Results confirm that knowledge about recommendations for cancer prevention is an important determinant for adherence and suggest that strategies to increase knowledge should be included in lifestyle promotion targeted at LS patients, along with behavior change techniques influencing other modifiable determinants.

Identifying the BRCA1 c.-107A > T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation - Vincent M. T. de Jong; Roelof Pruntel; Tessa G. Steenbruggen; Fonnet E. Bleeker; Petra Nederlof; Frans B. L. Hogervorst; Sabine C. linn (Familial Cancer, 2023)
An inherited single nucleotide variant (SNV) in the 5′UTR of the BRCA1 gene c.-107A > T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1 . We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation.

A pilot study investigating feasibility of mainstreaming germline BRCA1 and BRCA2 testing in high-risk patients with breast and/or ovarian cancer in three tertiary Cancer Centres in Ireland - Terri Patricia McVeigh; Karl J. Sweeney; Donal J. Brennan; Una M. McVeigh; Simon Ward; Ann Strydom; Sheila Seal; Katherine Astbury; Paul Donnellan; Joanne Higgins; Maccon Keane; Michael J. Kerin; et al. (Familial Cancer, 2023)

Disclosure of genetic risk to dating partners among young adults with von Hippel-Lindau disease - Elysa Bond; Beverly Yashar; Tobias Else; Jenae Osborne; Monica Marvin (Familial Cancer, 2023)

Analysis of uveal melanomas and paired constitutional DNA for exclusion of a BAP1-tumor predisposition syndrome - Yasaman Arjmand Abbassi; Claudia Le Guin; Norbert Bornfeld; Nikolaos E. Bechrakis; Michael Zeschnigk; Dietmar R. Lohmann (Familial Cancer, 2023)
Uveal melanoma (UM) is a rare tumor originating from melanocytic cells in the eye. Familial aggregation of UM is rare and can occur as part of the tumor predisposition syndrome BAP1-TPDS. However, family history alone will only identify a subset of patients with BAP1-TPDS. In the present study, we used sequential testing of tumor and blood DNA from UM patients for differential diagnosis of BAP1-TPDS. The study group was an unselected prospective cohort of patients from whom UM tissue was available. First, chromosome 3 status in tumor DNA was determined in all 140 patients who consented to participate. As tumors with disomy 3 rarely show BAP1 alterations, sequence analysis of this gene was performed in the 72 tumors with monosomy 3 (M3) or partial M3 only. We identified oncogenic BAP1 alterations in 52 of these tumors (72%). Targeted sequencing of DNA from matched peripheral blood showed pathogenic variants in two patients (3.8%) thus proving BAP1-TPDS. Only one of these two patients also had a medical history suggestive of this syndrome. Conversely, in three patients known to have had additional tumors before diagnosis of UM, constitutional heterozygosity for a BAP 1 mutation was excluded. Altogether, in 50 patients we could exclude BAP1-TPDS with high diagnostic certainty. The results of our study support that genetic testing for BAP1-TPDS should be offered to all patients with UM. Moreover, as genetic information from the tumor can help exclude heritable risk, the strategy for analysis should include efforts to obtain tumor samples for testing.

CDH1 mutations recurrence and global clustering in genetically tested families with hereditary diffuse gastric cancer syndrome: results from a systematic study - Giovanni Corso; Valentina Tagliaferri; Giulia Massari; Antonio Cioffi; Elisabetta Maria Cristina Rossi; Paolo Veronesi; Francesca Magnoni (Familial Cancer, 2023)

Endoscopic management of familial adenomatous polyposis targeting colorectal lesions greater than 5 mm in size: a single-center retrospective study - Tatsuro Murano; Hiroaki Ikematsu; Kensuke Shinmura; Kei Okumura; Takeshi Kuwata; Mineko Ushiama; Teruhiko Yoshida; Kenji Takashima; Keiichiro Nakajo; Tomohiro Kadota; Yusuke Yoda; Yasuhiro Oono; et al. (Familial Cancer, 2023)

Hepatocellular carcinoma and solid pseudopapillary neoplasm of the pancreas complicating familial adenomatous polyposis: two cases and review of the literature - Jessica El Halabi; Lisa LaGuardia; R. Matthew Walsh; Choon Hyuck David Kwon; K. V. Narayanan Menon; David Liska; Carol A. Burke (Familial Cancer, 2023)

Remote vs in-person BRCA1/2 non-carriers test disclosure: patients’ choice during Covid-19 pandemic restriction - Silvia Costanzo; Simona De Summa; Leonarda Maurmo; Maria Digennaro; Margherita Patruno; Angelo Paradiso (Familial Cancer, 2023)

Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes - Sietse M. Aukema; Selina Glaser; Mari F. C. M. van den Hout; Sonja Dahlum; Marinus J. Blok; Morten Hillmer; Julia Kolarova; Raf Sciot; Dina A. Schott; Reiner Siebert; Constance T. R. M. Stumpel (Familial Cancer, 2023)
Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5–10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.

Prevalence of FANCM germline variants in BRCA1/2 negative breast and/or ovarian cancer patients from Pakistan - Muhammad Usman Rashid; Noor Muhammad; Umara Shehzad; Faiz Ali Khan; Asif Loya; Ute Hamann (Familial Cancer, 2023)

A case of Rothmund-Thomson syndrome originally thought to be a case of Bloom syndrome - David Humberto Marmolejo Castañeda; Mara Cruellas Lapeña; Estela Carrasco López; Gloria Aparicio Español; Claudia Valverde Morales; Adrià López-Fernández; Eduard Pérez Ballesteros; Sara Torres-Esquius; Mónica Pardo Muñoz; Judith Balmaña Gelpi (Familial Cancer, 2023)

Universal tumor screening for lynch syndrome on colorectal cancer biopsies impacts surgical treatment decisions - Jennifer Vazzano; Jewel Tomlinson; Peter P. Stanich; Rachel Pearlman; Matthew F. Kalady; Wei Chen; Heather Hampel; Wendy L. Frankel (Familial Cancer, 2023)
Universal tumor screening (UTS) for Lynch syndrome (LS) on colorectal cancer (CRC) can be performed on biopsies or resection specimens. The advantage of biopsies is the chance to provide preoperative genetic counseling/testing (GC/T) so patients diagnosed with LS can make informed decisions regarding resection extent. We evaluated utilization of UTS on biopsies, percentage of patients with deficient mismatch repair (dMMR) who underwent GC/T preoperatively, and whether surgical/treatment decisions were impacted. We performed a retrospective review of medical records to assess CRC cases with dMMR immunohistochemical staining from 1/1/2017 to 2/26/2021. 1144 CRC patients had UTS using MMR immunohistochemistry; 559 biopsies (48.9%) and 585 resections (51.1%). The main reason UTS was not performed on biopsy was it occurred outside our health system. 58 (5%) of CRCs were dMMR and did not have MLH1 promoter hypermethylation (if MLH1 and PMS2 absent). 28/58 (48.3%) of dMMR cases were diagnosed on biopsy. Of those 28, 14 (50%) eventually underwent GC/T, and 7 (25%) had GT results prior to surgery. One of the 7 had incomplete documentation of results affecting their treatment plan. Of the remaining 6 with complete documentation, 5 underwent surgery and one was treated with immunotherapy only. Three patients elected a more extensive surgery. 6/28 (21.4%) dMMR patients identified on biopsy made an informed surgical/treatment decision based on their dMMR status/LS diagnosis. When applied, UTS on biopsy followed by genetic counseling and testing informs surgical decision-making. Process and implementation strategies are in place to overcome challenges to more broadly optimize this approach.

Potential risks associated with the use of ionizing radiation for imaging and treatment of colorectal cancer in Lynch syndrome patients - Mingzhu Sun; Jayne Moquet; Michele Ellender; Simon Bouffler; Christophe Badie; Rachel Baldwin-Cleland; Kevin Monahan; Andrew Latchford; David Lloyd; Susan Clark; Nicola A. Anyamene; Elizabeth Ainsbury; et al. (Familial Cancer, 2023)
The aim of this review is to investigate the literature pertaining to the potential risks of low-dose ionizing radiation to Lynch syndrome patients by use of computed tomography (CT), either diagnostic CT colonography (CTC), standard staging CT or CT surveillance. Furthermore, this review explores the potential risks of using radiotherapy for treatment of rectal cancer in these patients. No data or longitudinal observational studies of the impact of radiation exposure on humans with Lynch syndrome were identified. Limited experimental studies utilizing cell lines and primary cells exposed to both low and high radiation doses have been carried out to help determine radio-sensitivity associated with DNA mismatch repair gene deficiency, the defining feature of Lynch syndrome. On balance, these studies suggest that mismatch repair deficient cells may be relatively radio-resistant (particularly for low dose rate exposures) with higher mutation rates, albeit no firm conclusions can be drawn. Mouse model studies, though, showed an increased risk of developing colorectal tumors in mismatch repair deficient mice exposed to radiation doses around 2 Gy. With appropriate ethical approval, further studies investigating radiation risks associated with CT imaging and radiotherapy relevant doses using cells/tissues derived from confirmed Lynch patients or genetically modified animal models are urgently required for future clinical guidance.

Mainstreaming germline genetic testing for patients with pancreatic cancer increases uptake - Mitchell L. Ramsey; Jewel Tomlinson; Rachel Pearlman; Laith Abushahin; Amber Aeilts; Hui-Zi Chen; Yan Chen; Ashley Compton; Rifat Elkhatib; Levi Geiger; John Hays; Joanne Jeter; et al. (Familial Cancer, 2023)

A large family with MSH3-related polyposis - Arthur S. Aelvoet; Daniël R. Hoekman; Bert J. W. Redeker; Jitske Weegenaar; Evelien Dekker; Carel J. M. van Noesel; Floor A. M. Duijkers (Familial Cancer, 2023)
Biallelic MSH3 germline variants are a rare cause of adenomatous polyposis as yet reported in two small families only. We describe the phenotype of a third family, the largest thus far, with adenomatous polyposis related to compound heterozygous MSH3 pathogenic variants. The index patient was a 55-years old male diagnosed with rectal cancer and adenomatous polyposis (cumulatively 52 polyps), with a family history of colorectal polyposis with unknown cause. Next-generation sequencing and copy number variation analysis of a panel of genes associated with colorectal cancer and polyposis revealed compound heterozygous germline pathogenic variants in the MSH3 gene. Nine out of 11 siblings were genotyped. Three siblings carried the same compound heterozygous MSH3 variants. Colonoscopy screening showed predominantly right-sided adenomatous polyposis in all compound heterozygous siblings, with a cumulative number of adenomas ranging from 18 to 54 in an average of four colonoscopies, and age at first adenoma detection ranging from 46 to 59. Microsatellite analysis demonstrated alterations at selected tetranucleotide repeats (EMAST) in DNA retrieved from the rectal adenocarcinoma, colorectal adenomas as well as of normal colonic mucosa. Gastro-duodenoscopy did not reveal adenomas in any of the four patients. Extra-intestinal findings included a ductal adenocarcinoma in ectopic breast tissue in one female sibling at the age of 46, and liver cysts in three affected siblings. None of the three heterozygous or wild type siblings who previously underwent colonoscopy had adenomatous polyposis. We conclude that biallelic variants in MSH3 are a rare cause of attenuated adenomatous polyposis with an onset in middle age.

Prevalence and risk factors of barrett’s esophagus in lynch syndrome - Natalie Farha; Ruishen Lyu; David Liska; Amit Bhatt; Carole Macaron; Carol A. Burke (Familial Cancer, 2023)

Founder vs. non-founder BRCA1/2 pathogenic alleles: the analysis of Belarusian breast and ovarian cancer patients and review of other studies on ethnically homogenous populations - G. A. Yanus; E. L. Savonevich; A. P. Sokolenko; A. A. Romanko; V. I. Ni; E. Kh. Bakaeva; O. A. Gorustovich; I. V. Bizin; E. N. Imyanitov (Familial Cancer, 2023)

Truncating TINF2 p.Tyr312Ter variant and inherited breast cancer susceptibility - Susanna Koivuluoma; Sandra Vorimo; Tiina M. Mattila; Anna Tervasmäki; Timo Kumpula; Outi Kuismin; Robert Winqvist; Jukka Moilanen; Tuomo Mantere; Katri Pylkäs (Familial Cancer, 2023)
TINF2 is a critical subunit of the shelterin complex, which protects and maintains the length of telomeres. Pathogenic missense and truncating TINF2 mutations are causative for dyskeratosis congenita (DC), a rare, dominantly inherited bone marrow failure syndrome characterized by mucocutaneous abnormalities and cancer predisposition. Recent reports indicate that specific TINF2 truncating mutations act as high penetrance cancer predisposition alleles outside DC context, including breast cancer in their tumor spectrum. Here, we have evaluated the role of germline mutations in TINF2 and other shelterin genes in inherited breast cancer susceptibility using exome sequencing data from 98 Northern Finnish breast cancer cases with indication of inherited disease predisposition as a discovery cohort. A single protein truncating variant, TINF2 p.Tyr312Ter, was identified in one of the cases (1/98), and four more carriers were observed in the subsequently genotyped unselected breast cancer cohort (4/1904). None of the carriers were reported to have DC. TINF2 p.Tyr312Ter resulted in stable short form of mRNA transcript, and normal telomere length has been indicated by a recent report. Although recurrent in cases (total of 5/2095), TINF2 p.Tyr312Ter is also present in Finnish population controls (8/12,517), and the observed 4-fold higher frequency in cases falls at most into the range of moderate breast cancer risk alleles (OR 3.74, 95% CI 1.22–11.45, p = 0.029). Current results indicate that not all TINF2 truncating variants are high cancer risk alleles and add further evidence that different TINF2 mutations can have very diverse effects on the disease phenotype.

Healthcare professionals’ perspectives on implementation of universal tumor DNA testing in ovarian cancer patients: multidisciplinary focus groups - Vera M. Witjes; Jozé C. C. Braspenning; Nicoline Hoogerbrugge; Yvonne H. C. M. Smolders; Dorien M. A. Hermkens; Marian J. E. Mourits; Marjolijn J. L. Ligtenberg; Margreet G. E. M. Ausems; Joanne A. de Hullu (Familial Cancer, 2023)
Universal tumor DNA testing in epithelial ovarian cancer patients can function not only as an efficient prescreen for hereditary cancer testing, but may also guide treatment choices. This innovation, introduced as Tumor-First workflow, offers great opportunities, but ensuring optimal multidisciplinary collaboration is a challenge. We investigated factors that were relevant and important for large-scale implementation. In three multidisciplinary online focus groups, healthcare professionals (gynecologic oncologists, pathologists, clinical geneticists, and clinical laboratory specialists) were interviewed on factors critical for the implementation of the Tumor-First workflow. Recordings were transcribed for analysis in Atlas.ti according to the framework of Flottorp that categorizes seven implementation domains. Healthcare professionals from all disciplines endorse implementation of the Tumor-First workflow, but more detailed standardization and advice regarding the logistics of the workflow were needed. Healthcare professionals explored ways to stay informed about the different phases of the workflow and the results. They emphasized the importance of including all epithelial ovarian cancer patients in the workflow and monitoring this inclusion. Overall, healthcare professionals would appreciate supporting material for the implementation of the Tumor-First workflow in the daily work routine. Focus group discussions have revealed factors for developing a tailored implementation strategy for the Tumor-First workflow in order to optimize care for epithelial ovarian cancer patients. Future innovations affecting multidisciplinary oncology teams including clinical geneticists can benefit from the lessons learned.

Preimplantation genetic testing in patients with genetic susceptibility to cancer - Marie-Charlotte Villy; Nelly Frydman; Céline Moutou; Gaëlle Thierry; Jade Raad; Chrystelle Colas; Julie Steffann; Julie Metras; Nathalie Chabbert-Buffet; Yann Parc; Stéphane Richard; Patrick R. Benusiglio (Familial Cancer, 2023)

InSiGHT 2022 Abstract Publishing and Best Abstract Awards (Familial Cancer, 2022)

Long-term chemoprevention in patients with adenomatous polyposis coli: an observational study - Teresa M. Neuhann; Katharina Haub; Verena Steinke-Lange; Monika Morak; Andreas Laner; Melanie Locher; Elke Holinski-Feder (Familial Cancer, 2022)

Collaborative Group of the Americas on Inherited Gastrointestinal Cancers (CGA-IGC) Annual Virtual Meeting, November 13–15, 2021 (Familial Cancer, 2022)

Intestinal and extraintestinal neoplasms in patients with NTHL1 tumor syndrome: a systematic review - S. H. Beck; A. M. Jelsig; H. M. Yassin; L. J. Lindberg; K. A. W. Wadt; J. G. Karstensen (Familial Cancer, 2022)

Juvenile polyposis diagnosed with an integrated histological, immunohistochemical and molecular approach identifying new SMAD4 pathogenic variants - Andrea Mafficini; Lodewijk A. A. Brosens; Maria L. Piredda; Cristian Conti; Paola Mattiolo; Giulia Turri; Maria G. Mastrosimini; Sara Cingarlini; Stefano F. Crinò; Matteo Fassan; Paola Piccoli; Michele Simbolo; et al. (Familial Cancer, 2022)
Juvenile polyposis (JP) is a rare familial syndrome characterized by the development of numerous hamartomatous polyps of the gastrointestinal tract and by an increased risk of developing gastrointestinal cancers. It follows a pattern of autosomal dominant inheritance and is associated with germline variants of SMAD4 or BMPR1A genes. Differential diagnosis may be difficult based on histology alone, due to morphological similarities to other familial syndromes. Here we report a case of familial JP diagnosed in a 50-years woman with a familial history positive for gastrointestinal cancers and other tumor types. The patient presented with severe iron deficiency anemia and showed numerous polyps in the stomach and jejunum according to endoscopy and imaging. She underwent an intra-gastric laparoscopic removal of the major gastric polyp, followed by jejunal exploration and resection of a segment with multiple neoformations. Histological examination revealed the presence of hamartomatous polyposis. Gastric and intestinal samples were analyzed with next-generation sequencing. Molecular analysis showed that the patient harbored a germline splicing site variant of SMAD4 , c.1139 + 3A > G, which was complemented by different somatic variants of the same gene in the different polyps. Immunohistochemistry for SMAD4 confirmed loss of protein expression in the polyps, with regular expression in normal cells. cDNA sequencing further confirmed the findings. We thus definitively diagnosed the woman as having JP thanks to an integrated approach based on histology, immunohistochemistry and molecular analysis. The identified variants, all previously reported as variants of unknown significance, were classified as pathogenic as they complemented each other leading to SMAD4 loss.

Physicians’ experience, practice and education, on genetic testing and genetic counseling: a nationwide survey study in Greece - Elena Fountzilas; Paraskevi Apostolou; Angelo V. Vasiliadis; Dimitra Aivazi; Emmanouil Saloustros; Florentia Fostira (Familial Cancer, 2022)

Colectomy and desmoid tumours in familial adenomatous polyposis: a systematic review and meta-analysis - Arthur S. Aelvoet; Daphne Struik; Barbara A. J. Bastiaansen; Willem A. Bemelman; Roel Hompes; Patrick M. M. Bossuyt; Evelien Dekker (Familial Cancer, 2022)
Desmoid tumours (DT) are one of the main causes of death in patients with familial adenomatous polyposis (FAP). Surgical trauma is a risk factor for DT, yet a colectomy is inevitable in FAP to prevent colorectal cancer. This systematic review and meta-analysis aimed to synthesize the available evidence on DT risk related to type, approach and timing of colectomy. A search was performed in MEDLINE, EMBASE and the Cochrane Library. Studies were considered eligible when DT incidence was reported after different types, approaches and timing of colectomy. Twenty studies including 6452 FAP patients were selected, all observational. No significant difference in DT incidence was observed after IRA versus IPAA (OR 0.99, 95% CI 0.69–1.42) and after open versus laparoscopic colectomy (OR 0.88, 95% CI 0.42–1.86). Conflicting DT incidences were seen after early versus late colectomy and when analysing open versus laparoscopic colectomy according to colectomy type. Three studies reported a (non-significantly) higher DT incidence after laparoscopic IPAA compared to laparoscopic IRA, with OR varying between 1.77 and 4.09. A significantly higher DT incidence was observed in patients with a history of abdominal surgery (OR 3.40, 95% CI 1.64–7.03, p = 0.001). Current literature does not allow to state firmly whether type, approach, or timing of colectomy affects DT risk in FAP patients. Fewer DT were observed after laparoscopic IRA compared to laparoscopic IPAA, suggesting laparoscopic IRA as the preferred choice if appropriate considering rectal polyp burden. PROSPERO registration number CRD42020161424.

Detecting inversions in routine molecular diagnosis in MMR genes - Edwige Kasper; Sophie Coutant; Sandrine Manase; Stéphanie Vasseur; Pierre Macquère; Gaëlle Bougeard; Laurence Faivre; Olivier Ingster; Stéphanie Baert-Desurmont; Claude Houdayer (Familial Cancer, 2022)

BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories - Henrikke N. Hovland; Rafal Al-Adhami; Sarah Louise Ariansen; Marijke Van Ghelue; Wenche Sjursen; Sigrid Lima; Marte Bolstad; Amund H. Berger; Hildegunn Høberg-Vetti; Per Knappskog; Bjørn Ivar Haukanes; Ingvild Aukrust; et al. (Familial Cancer, 2022)
Pathogenic germline variants in Breast cancer susceptibility gene 1 ( BRCA1 ) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1–5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2–5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment.

Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer - Amanda Bartenbaker Thompson; Erin G. Sutcliffe; Kevin Arvai; Maegan E. Roberts; Lisa R. Susswein; Megan L. Marshall; Rebecca Torene; Kristen J. Vogel Postula; Kathleen S. Hruska; Shaochun Bai (Familial Cancer, 2022)

Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer - James M. Chan; Mark Clendenning; Sharelle Joseland; Peter Georgeson; Khalid Mahmood; Romy Walker; Julia Como; Jihoon E. Joo; Susan Preston; Ryan A. Hutchinson; Bernard J. Pope; Andrew Metz; et al. (Familial Cancer, 2022)

Medullary thyroid cancer and pheochromocytoma in MEN2A: are there parent of origin effects on disease expression? - Andreas Machens; Kerstin Lorenz; Frank Weber; Henning Dralle (Familial Cancer, 2022)

Correction to: 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, 2022)

Identification of women at risk of hereditary breast–ovarian cancer among participants in a population-based breast cancer screening - Luigina Bonelli; Ivana Valle; Ivana Rebora; Paola Ricci; Lidia Biocchi; Giovanna Bruschi; Sabrina Parodi; Carla Bruzzone; Liliana Varesco (Familial Cancer, 2022)

Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes? - Janni M. Jensen; Anne Skakkebæk; Mette Gaustadness; Mette Sommerlund; Hans Gjørup; Ken Ljungmann; Charlotte K. Lautrup; Lone Sunde (Familial Cancer, 2022)

Re-evaluating cancer risks associated with the CHEK2 p.Ser428Phe Ashkenazi Jewish founder pathogenic variant - Yael Laitman; Sarah M. Nielsen; Kathryn E. Hatchell; Rebecca Truty; Rinat Bernstein-Molho; Edward D. Esplin; Eitan Friedman (Familial Cancer, 2022)

Positive experiences of healthcare professionals with a mainstreaming approach of germline genetic testing for women with ovarian cancer - Kyra Bokkers; Ronald P. Zweemer; Marco J. Koudijs; Sanne Stehouwer; Mary E. Velthuizen; Eveline M. A. Bleiker; Margreet G. E. M. Ausems (Familial Cancer, 2022)
According to current guidelines, all women with epithelial ovarian cancer are eligible for genetic testing for BRCA germline pathogenic variants. Unfortunately, not all affected women are tested. We evaluated the acceptability and feasibility for non-genetic healthcare professionals to incorporate germline genetic testing into their daily practice. We developed and implemented a mainstreaming pathway, including a training module, in collaboration with various healthcare professionals and patient organizations. Healthcare professionals from 4 different hospitals were invited to participate. After completing the training module, gynecologic oncologists, gynecologists with a subspecialty training in oncology, and nurse specialists discussed and ordered genetic testing themselves. They received a questionnaire before completing the training module and 6 months after working according to the new pathway. We assessed healthcare professionals’ attitudes, perceived knowledge, and self-efficacy, along with the feasibility of this new mainstream workflow in clinical practice, and evaluated the use and content of the training module. The participation rate for completing the training module was 90% (N = 19/21). At baseline and after 6 months, healthcare professionals had a positive attitude, high perceived knowledge and high self-efficacy toward discussing and ordering genetic testing. Knowledge had increased significantly after 6 months. The training module was rated with an average of 8.1 out of 10 and was considered useful. The majority of healthcare professionals (9/15) was able to discuss a genetic test in five to 10 min. After completion of a training module, non-genetic healthcare professionals feel motivated and competent to discuss and order genetic testing themselves.

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, 2022)

Eighth International Symposium on hereditary breast and ovarian cancer (Familial Cancer, 2022)

Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome - Hannah Dawson; Alannah Smrke; Peter M. Ellery; Nafisa Wilkinson; Adam N. Rosenthal; Terri P. McVeigh (Familial Cancer, 2022)

A de novo pathogenic variant in the MSH6 gene in a 52 years-old woman - Elise Pierre-Noël; Fabrice Airaud; Estelle Cauchin; Céline Garrec; Ingrid Ricordeau; Clémence Michon; Olivier Kerdraon; Stéphane Bezieau; Caroline Abadie (Familial Cancer, 2022)

Uterine leiomyomatosis in adolescents and young adults (AYAs) may represent a narrow phenotypic variant of FH tumour predisposition syndrome - Tiffany Foo; Vivek Nama; Ayoma D. Attygalle; Jonathan Williams; Kara Heelan; Samantha Butler; Terri P. McVeigh (Familial Cancer, 2022)

Patient ethnicity and cascade genetic testing: a descriptive study of a publicly funded hereditary cancer program - Eryn F. Braley; Angela C. Bedard; Jennifer Nuk; Quan Hong; James E. J. Bedard; Sophie Sun; Kasmintan A. Schrader (Familial Cancer, 2022)

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family - Kevin M. Brown; Mai Xu; Michael Sargen; Hyunbum Jang; Mingzhen Zhang; Tongwu Zhang; Bin Zhu; Kristie Jones; Jung Kim; Laura Mendoza; Nicholas K. Hayward; Margaret A. Tucker; et al. (Familial Cancer, 2022)

PTCH2 is not a strong candidate gene for gorlin syndrome predisposition - Miriam J. Smith; D. Gareth Evans (Familial Cancer, 2022)
A number of case/family reports have proposed PTCH2 as a putative Gorlin Syndrome (GS) gene, but evidence to support this is lacking. We assessed our cohort of 21 PTCH1/SUFU negative GS families for PTCH2 variants and assessed current evidence from reported cases/families and population data. In our PTCH1/SUFU variant negative GS cohort (25% of total), no pathogenic or likely pathogenic PTCH2 variants were identified. In addition, none of the previously published PTCH2 variants in GS families/cases could be considered pathogenic or likely pathogenic using current guidelines. The absence of clear pathogenic variants in GS families and the high frequency of Loss-of-function (LoF) variants in the general population, including the presence of homozygous LoF variants without a clinical phenotype, mean that it is untenable that PTCH2 is a GS gene. PTCH2 should not be included in panels for genetic diagnosis of GS.

A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven - Rieko Taniguchi; Hideki Muramatsu; Yusuke Okuno; Taro Yoshida; Manabu Wakamatsu; Motoharu Hamada; Chiyoe Shirota; Wataru Sumida; Akinari Hinoki; Takahisa Tainaka; Yoshimitsu Gotoh; Toyonori Tsuzuki; et al. (Familial Cancer, 2022)

Utility of interim blood tests for cancer screening in Li-Fraumeni syndrome - Leatrisse Oba; Ana F. Best; Phuong L. Mai; Maria Isabel Achatz; Paul S. Albert; Sharon A. Savage; Payal P. Khincha (Familial Cancer, 2022)

A recurrent pathogenic BRCA2 exon 5–11 duplication in the Christian Arab population in Israel - Gili Reznick Levi; Gal Larom; Vered Ofen Glassner; Nina Ekhilevitch; Nitzan Sharon Swartzman; Tamar Paperna; Hagit Baris-Feldman; Karin Weiss (Familial Cancer, 2022)

Recurring pathogenic variants in the BRCA2 gene in the Ethiopian Jewish population. Founder mutations? - Mark D. Ludman; Shira Litz Philipsborn; Shulamit Hartmajer; Nitzan Sharon Shwartzman; Eyal Reinstein (Familial Cancer, 2022)

First international workshop of the ATM and cancer risk group (4-5 December 2019) - Fabienne Lesueur; Douglas F. Easton; Anne-Laure Renault; Sean V. Tavtigian; Jonine L. Bernstein; Zsofia Kote-Jarai; Rosalind A. Eeles; Dijana Plaseska-Karanfia; Lidia Feliubadaló; Alejandro Moles-Fernández; Marta Santamariña-Pena; Alysson T. Sánchez; et al. (Familial Cancer, 2022)

Questioning the validity of clinically available breast cancer polygenic risk scores: comparison of two labs reveals discrepancies - Julia Wynn; Elana Levinson; Carrie Koval; Michelle E. Ernst; Wendy K. Chung (Familial Cancer, 2022)

Pilot study of an online training program to increase genetic literacy and communication skills in oncology healthcare professionals discussing BRCA1/2 genetic testing with breast and ovarian cancer patients - Bettina Meiser; Paula Woodward; Margaret Gleeson; Maira Kentwell; Helen Mar Fan; Yoland Antill; Phyllis N. Butow; Frances Boyle; Megan Best; Natalie Taylor; Katy Bell; Kathy Tucker (Familial Cancer, 2022)

The psychological impact and experience of breast cancer screening in young women with an increased risk of breast cancer due to neurofibromatosis type 1 - Ashley Crook; Rebekah Kwa; Sarah Ephraums; Mathilda Wilding; Lavvina Thiyagarajan; Jane Fleming; Katrina Moore; Yemima Berman (Familial Cancer, 2022)

The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management - Claire Palles; Lynn Martin; Enric Domingo; Laura Chegwidden; Josh McGuire; Vicky Cuthill; Ellen Heitzer; Rachel Kerr; David Kerr; Stephen Kearsey; Susan K. Clark; Ian Tomlinson; et al. (Familial Cancer, 2022)
Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE , 27 POLD1 ). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1- mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients.

CDH1 pathogenic variants and cancer risk in an unselected patient population - Ariel Bar-Mashiah; Emily R. Soper; Sinead Cullina; Gillian M. Belbin; Eimear E. Kenny; Aimee L. Lucas; Noura S. Abul-Husn (Familial Cancer, 2022)

Von Hippel-Lindau disease and rapidly progressing pheochromocytomas in siblings - Ioana Fugaru; Catherine Goudie; John-Paul Capolicchio (Familial Cancer, 2022)

“I wish that there was more info”: characterizing the uncertainty experienced by carriers of pathogenic ATM and/or CHEK2 variants - Kathryn G. Reyes; Cheyla Clark; Meredith Gerhart; Ainsley J. Newson; Kelly E. Ormond (Familial Cancer, 2022)

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer - I. Kedar; L. Walsh; G. Reznick Levi; S. Lieberman; A. Abu Shtaya; S. Naftaly Nathan; I. Lagovsky; R. Tomashov-Matar; M. Goldenberg; L. Basel-Salmon; L. Katz; O. Aleme; et al. (Familial Cancer, 2022)

Malignancy risk in individuals with familial adenomatous polyposis receiving biologics and immunomodulators - Muhammad Salman Faisal; Carol A. Burke; Jean-Paul Achkar; Benjamin Click; Margaret O’Malley; Lisa LaGuardia; Susan Milicia; Brandie Leach; David Liska; James Church; Matthew Kalady; Gautam Mankaney (Familial Cancer, 2022)

Extended gene panel testing in lobular breast cancer - Elke M. van Veen; D. Gareth Evans; Elaine F. Harkness; Helen J. Byers; Jamie M. Ellingford; Emma R. Woodward; Naomi L. Bowers; Andrew J. Wallace; Sacha J. Howell; Anthony Howell; Fiona Lalloo; William G. Newman; et al. (Familial Cancer, 2022)
Purpose : Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods : 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53. Results : 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2 . Ten actionable PGVs were identified in additional genes ( ATM (4), CDH1 (1), CHEK2 (1), PALB2 (2) and TP53 (2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1 : OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2 : OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2 . Conclusion : The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population - Kathleen F. Mittendorf; Chinedu Ukaegbu; Marian J. Gilmore; Nangel M. Lindberg; Tia L. Kauffman; Donna J. Eubanks; Elizabeth Shuster; Jake Allen; Carmit McMullen; Heather Spencer Feigelson; Katherine P. Anderson; Michael C. Leo; et al. (Familial Cancer, 2022)
Lynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM 5 ™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM 5 ™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM 5 ™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk.

A comprehensive reference for BRCA1/2 genes pathogenic variants in Iran: published, unpublished and novel - Keivan Majidzadeh-A; Shiva Zarinfam; Nasrin Abdoli; Fatemeh Yadegari; Rezvan Esmaeili; Leila Farahmand; Azin Teimourzadeh; Mahdieh Taghizadeh; Mansoor Salehi; Mohamad Zamani (Familial Cancer, 2022)

Age of diagnosis in familial Barrett’s associated neoplasia - Benita K. Glamour; Omar Alaber; Gino Cioffi; Apoorva K. Chandar; Jill Barnholtz-Sloan; Wendy Brock; Gary W. Falk; Marcia I. Canto; Jean S. Wang; Prasad G. Iyer; Nicholas J. Shaheen; William M. Grady; et al. (Familial Cancer, 2022)

Knowledge and psychosocial impact of genetic counseling and multigene panel testing among individuals with ovarian cancer - Rachel A. Pozzar; Fangxin Hong; Niya Xiong; Jill E. Stopfer; Manan M. Nayak; Meghan Underhill-Blazey (Familial Cancer, 2022)

Use of sanger and next-generation sequencing to screen for mosaic and intronic APC variants in unexplained colorectal polyposis patients - Fadwa A. Elsayed; Carli M. J. Tops; Maartje Nielsen; Hans Morreau; Frederik J. Hes; Tom van Wezel (Familial Cancer, 2022)
In addition to classic germline APC gene variants, APC mosaicism and deep intronic germline APC variants have also been reported to be causes of adenomatous polyposis. In this study, we investigated 80 unexplained colorectal polyposis patients without germline pathogenic variants in known polyposis predisposing genes to detect mosaic and deep intronic APC variants. All patients developed more than 50 colorectal polyps, with adenomas being predominantly observed. To detect APC mosaicism, we performed next-generation sequencing (NGS) in leukocyte DNA. Furthermore, using Sanger sequencing, the cohort was screened for the following previously reported deep intronic pathogenic germline APC variants: c.1408 + 731C > T, p.(Gly471Serfs*55), c.1408 + 735A > T, p.(Gly471Serfs*55), c.1408 + 729A > G, p.(Gly471Serfs*55) and c.532-941G > A, p.(Phe178Argfs*22). We did not detect mosaic or intronic APC variants in the screened unexplained colorectal polyposis patients. The results of this study indicate that the deep intronic APC variants investigated in this study are not a cause of colorectal polyposis in this Dutch population. In addition, NGS did not detect any further mosaic variants in our cohort.

Managing gastric cancer risk in lynch syndrome: controversies and recommendations - C. Richard Boland; Matthew B. Yurgelun; Kathryn A. Mraz; Patrick M. Boland (Familial Cancer, 2022)

The needs of Southeast Asian BRCA mutation carriers considering risk-reducing salpingo-oophorectomy: a qualitative study - Hamizah Sa’at; Yew-Kong Lee; Sook-Yee Yoon; Siu Wan Wong; Yin Ling Woo; Kristine Barlow-Stewart; Nur Aishah Mohd Taib (Familial Cancer, 2022)

Approach to screening for Familial Adenomatous Polyposis (FAP) in a cohort of 226 patients with Desmoid-type Fibromatosis (DF): experience of a specialist center in the UK - E. Cojocaru; S. Gennatas; K. Thway; C. Fisher; A. Smrke; D. Strauss; A. Hayes; M. Smith; R. L. Jones; C. Benson; T. P. McVeigh (Familial Cancer, 2022)

Genetic predisposition to prostate cancer: an update - Holly Ni Raghallaigh; Rosalind Eeles (Familial Cancer, 2022)
Improvements in DNA sequencing technology and discoveries made by large scale genome-wide association studies have led to enormous insight into the role of genetic variation in prostate cancer risk. High-risk prostate cancer risk predisposition genes exist in addition to common germline variants conferring low-moderate risk, which together account for over a third of familial prostate cancer risk. Identifying men with additional risk factors such as genetic variants or a positive family history is of clinical importance, as men with such risk factors have a higher incidence of prostate cancer with some evidence to suggest diagnosis at a younger age and poorer outcomes. The medical community remains in disagreement on the benefits of a population prostate cancer screening programme reliant on PSA testing. A reduction in mortality has been demonstrated in many studies, but at the cost of significant amounts of overdiagnosis and overtreatment. Developing targeted screening strategies for high-risk men is currently the subject of investigation in a number of prospective studies. At present, approximately 38% of the familial risk of PrCa can be explained based on published SNPs, with men in the top 1% of the risk profile having a 5.71-fold increase in risk of developing cancer compared with controls. With approximately 170 prostate cancer susceptibility loci now identified in European populations, there is scope to explore the clinical utility of genetic testing and genetic-risk scores in prostate cancer screening and risk stratification, with such data in non-European populations eagerly awaited. This review will focus on both the rare and common germline genetic variation involved in hereditary and familial prostate cancer, and discuss ongoing research in exploring the role of targeted screening in this high-risk group of men.

Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis - Paola Nix; Erin Mundt; Bradford Coffee; Elizabeth Goossen; Bryan M. Warf; Krystal Brown; Karla Bowles; Benjamin Roa (Familial Cancer, 2022)
A substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations ( BRCA2 c.68-3T>G, c.68-2A>G, c.425G>T, c.8331+2T>C). Evidence supporting a pathogenic classification is available for each variant, including in silico models, absence in population databases, and published functional data. However, comprehensive RNA analysis showed that some functional transcript may be produced by each variant. BRCA2 c.68-3T>G results in a partial splice defect. For BRCA2 c.68-2A>G and c.425G>T, aberrant splicing was shown to produce a potentially functional, in-frame transcript. BRCA2 c.8331+2T>C may utilize a functional GC donor in place of the wild-type GT donor. The severity of cancer history for carriers of these variants was also assessed using a history weighting algorithm and was not consistent with pathogenic controls (carriers of known pathogenic variants in BRCA2 ). Due to the conflicting evidence, our laboratory classifies these BRCA2 variants as variants of uncertain significance. This highlights the importance of evaluating new and existing evidence to ensure accurate variant classification and appropriate patient care.

Progress Report: New insights into the prevention of CRC by colonoscopic surveillance in Lynch syndrome - Hans F. A. Vasen (Familial Cancer, 2022)

Comparison of universal screening in major lynch-associated tumors: a systematic review of literature - George Kunnackal John; Vipin Das Villgran; Christine Caufield-Noll; Francis M. Giardiello (Familial Cancer, 2022)

Genetic evaluation of patients and families with concern for hereditary endocrine tumor syndromes - Jennifer L. Anderson; Robert Pilarski; Lawrence Kirschner; Pamela Brock (Familial Cancer, 2022)

Atypical choroidal nevus in a subject with a germline PALB2 pathogenic variant - Timothy W. Grosel; Matthew Karl; Robert T. Pilarski; Frederick H. Davidorf; Mohamed H. Abdel-Rahman; Colleen M. Cebulla (Familial Cancer, 2022)

Correction to: Infantile fibrosarcoma with TPN3-NTRK3 fusion in a boy with Bloom Syndrome - Sue M. Huson; Timo Staab; Marta Pereira; Heather Ward; Roberto Paredes; D. Gareth Evans; Daniel Baumhoer; James O’Sullivan; Ed Cheesman; Detlev Schindler; Stefan Meyer (Familial Cancer, 2022)

Infantile fibrosarcoma with TPM3-NTRK1 fusion in a boy with Bloom syndrome - Sue M. Huson; Timo Staab; Marta Pereira; Heather Ward; Roberto Paredes; D. Gareth Evans; Daniel Baumhoer; James O’Sullivan; Ed Cheesman; Detlev Schindler; Stefan Meyer (Familial Cancer, 2022)
Bloom syndrome (BS) is a genomic and chromosomal instability disorder with prodigious cancer predisposition caused by pathogenic variants in BLM . We report the clinical and genetic details of a boy who first presented with infantile fibrosarcoma (IFS) at the age of 6 months and subsequently was diagnosed with BS at the age of 9 years. Molecular analysis identified the pathogenic germline BLM sequence variants (c.1642C>T and c.2207_2212delinsTAGATTC). This is the first report of IFS related to BS, for which we show that both BLM alleles are maintained in the tumor and demonstrate a TPM3-NTKR1 fusion transcript in the IFS. Our communication emphasizes the importance of long-term follow up after treatment for pediatric neoplastic conditions, as clues to important genetic entities might manifest later, and the identification of a heritable tumor predisposition often leads to changes in patient surveillance and management.

Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group - Jette J. Bakhuizen; Helen Hanson; Karin van der Tuin; Fiona Lalloo; Marc Tischkowitz; Karin Wadt; Marjolijn C. J. Jongmans; Beate B. Dörgeloh; Roula A. Farah; Stavros Glentis; Lisa Golmard; Juliane Hoyer; et al. (Familial Cancer, 2021)
DICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging because uncertainty exists about the clinical efficacy of surveillance, and appraisal of potential benefits and harms vary. In addition, there is increasing evidence that germline DICER1 pathogenic variants are associated with lower penetrance for cancer than previously assumed. To address these issues and to harmonize DICER1 syndrome surveillance programs within Europe, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) and Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom reviewed current surveillance strategies and evaluated additional relevant literature. Consensus was achieved for a new surveillance protocol and information leaflet that informs patients about potential symptoms of DICER1 -associated tumors. The surveillance protocol comprises a minimum program and an extended version for consideration. The key recommendations of the minimum program are: annual clinical examination from birth to age 20 years, six-monthly chest X-ray and renal ultrasound from birth to age 6 years, and thyroid ultrasound every 3 years from age 8 to age 40 years. The surveillance program for consideration comprises additional surveillance procedures, and recommendations for DICER1 pathogenic variant carriers outside the ages of the surveillance interval. Patients have to be supported in choosing the surveillance program that best meets their needs. Prospective evaluation of the efficacy and patient perspectives of proposed surveillance recommendations is required to expand the evidence base for DICER1 surveillance protocols.

The paradigm of hematological malignant versus non-malignant manifestations, driven by primary immunodeficiencies: a complex interplay - C. Kelaidi; V. Tzotzola; S. Polychronopoulou (Familial Cancer, 2021)

Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel - Anna Byrjalsen; Illja J. Diets; Jette Bakhuizen; Thomas van Overeem Hansen; Kjeld Schmiegelow; Anne-Marie Gerdes; Ulrik Stoltze; Roland P. Kuiper; Johannes H. M. Merks; Karin Wadt; Marjolijn Jongmans (Familial Cancer, 2021)
Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.

Review of guidelines for the identification and clinical care of patients with genetic predisposition for hematological malignancies - Brigitte Schlegelberger; Cristina Mecucci; Marcin Wlodarski (Familial Cancer, 2021)
Since WHO has recognized myeloid neoplasms with germline predisposition as a new entity in 2016, it has become increasingly clear that diagnosing familial leukemia has critical implications for both the patient and his/her family, and that interdisciplinary teams of hematologists and clinical geneticists should provide care for this specific patient group. Here, we summarize consensus criteria for the identification and screening of patients with genetic predisposition for hematologic malignancies, as provided by different working groups, e.g. by the Nordic MDS group and the AACR. In addition to typical clinical features, results from targeted deep sequencing may point to a genetic predisposition. We review strategies to distinguish somatic and germline variants and discuss recommendations for genetic analyses aiming to identify the underlying genetic variant that should follow established quality criteria to detect both SNVs and CNVs and to determine the pathogenicity of genetic variants. To enhance the knowledge about hematologic neoplasms with germline predisposition we recommend archiving clinical and genetic data and archiving them in international registries.

Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review - Agata Pastorczak; Karolina Krajewska; Zuzanna Urbanska; Bartosz Szmyd; Elzbieta Salacinska-Los; Józef Kobos; Wojciech Mlynarski; Joanna Trelinska (Familial Cancer, 2021)
Ovarian carcinoma is an extremely rare malignancy in children, often developing on the underlying inherited background. Female carriers of pathogenic germline mutations of SMARCA4 are at risk of an aggressive type of undifferentiated ovarian cancer called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Regardless of age of the patient, stage of the disease, and oncological treatment, the prognosis for SCCOHT is poor. Therefore, early intervention with risk-reducing surgeries is recommended for these patients . In this study, we report genetic testing of a family with two children carrying pathogenic germline mutations of SMARCA4 and summarize the course of SCCOHT in all pediatric patients reported in the literature with constitutional defects identified within the SMARCA4 locus.

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG) - L. Guerrini-Rousseau; M. J. Smith; C. P. Kratz; B. Doergeloh; S. Hirsch; S. M. J. Hopman; M. Jorgensen; M. Kuhlen; O. Michaeli; T. Milde; V. Ridola; A. Russo; et al. (Familial Cancer, 2021)
Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway ( PTCH1 or SUFU) , is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU -related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1 , and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

Constitutional 2p16.3 deletion including MSH6 and FBXO11 in a boy with developmental delay and diffuse large B-cell lymphoma - N. van Engelen; F. van Dijk; E. Waanders; A. Buijs; M. A. Vermeulen; J. L. C. Loeffen; R. P. Kuiper; M. C. J. Jongmans (Familial Cancer, 2021)
We describe a case of a boy with neurodevelopmental delay and a diffuse large B-cell lymphoma (DLBCL) in whom we discovered a germline de novo 2p16.3 deletion including MSH6 and part of the FBXO11 gene. A causative role for MSH6 in cancer development was excluded based on tumor characteristics. The constitutional FBXO11 deletion explains the neurodevelopmental delay in the patient. The FBXO11 protein is involved in BCL-6 ubiquitination and BCL-6 is required for the germinal center reaction resulting in B cell differentiation. Somatic loss of function alterations of FBXO11 result in BCL-6 overexpression which is a known driver in DLBCL. We therefore consider that a causative relationship between the germline FBXO11 deletion and the development of DLBCL in this boy is conceivable.

Correction to: Choose and stay on one out of two paths: distinction between clinical versus research genetic testing to identify cancer predisposition syndromes among patients with cancer - Tim Ripperger; D. Gareth Evans; David Malkin; Christian P. Kratz (Familial Cancer, 2021)

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study - Floor A. M. Postema; Saskia M. J. Hopman; Corianne A. J. M. de Borgie; Cora M. Aalfs; Jakob K. Anninga; Lieke P. V. Berger; Fonnet E. Bleeker; Charlotte J. Dommering; Natasha K. A. van Eijkelenburg; Peter Hammond; Marry M. van den Heuvel-Eibrink; Janna A. Hol; et al. (Familial Cancer, 2021)
Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.

Effective identification of cancer predisposition syndromes in children with cancer employing a questionnaire - Miriam Schwermer; Astrid Behnert; Beate Dörgeloh; Tim Ripperger; Christian P. Kratz (Familial Cancer, 2021)
Approximately 10% of children with newly diagnosed cancer have a cancer predisposition syndrome (CPS). The optimal diagnostic approach to identify them among children diagnosed with cancer is unknown. Objective : To determine whether the use of a one-page questionnaire can improve the CPS diagnosis among children with an oncologic condition. Design : Comparative effectiveness research. Setting : Referral center for children with cancer. Results : 739 children diagnosed with an oncologic condition between 2012 and 2019. All children with a newly diagnosed oncologic condition presenting to Hannover Medical School between January 1st 2017 and December 31st 2019 were prospectively evaluated with a CPS questionnaire. Children in whom the questionnaire suggested the need of a genetic workup were further evaluated. All children diagnosed with an oncologic condition between January 1st 2012 and December 31st 2016 served as control. The CPS diagnoses established during both time periods were evaluated and compared. A CPS was diagnosed in 27 out of 287 children (9.4%) during the questionnaire period versus 24 out of 452 children (5.3%) during the control period ( P = 0.032). Conclusion : The CPS questionnaire appears to significantly improve the diagnosis of children with CPS among children with a newly diagnosed oncologic condition.

Proportion of children with cancer that have an indication for genetic counseling and testing based on the cancer type irrespective of other features - Thi Minh Kha Nguyen; Astrid Behnert; Torsten Pietsch; Christian Vokuhl; Christian Peter Kratz (Familial Cancer, 2021)
In children with cancer, specific clinical features such as physical anomalies, occurrence of cancer in young relatives, specific cancer histologies, and unique mutation/methylation signatures may indicate the presence of an underlying cancer predisposition syndrome (CPS). The proportion of children with a cancer type suggesting a CPS among all children with cancer is unknown. To determine the proportion of children with cancer types suggesting an underlying CPS among children with cancer. We evaluated the number of children with cancer types strongly associated with CPS diagnosed in Germany between 2007 and 2016. Data were obtained from various sources including two national pediatric pathology reference laboratories for brain and solid tumors, respectively, various childhood cancer trial offices as well as the German Childhood Cancer Registry. Among 21,127 children diagnosed with cancer between 2007 and 2016, 2554 (12.1%) had a cancer type strongly associated with a CPS. The most common diagnoses were myelodysplastic syndrome and juvenile myelomonocytic leukemia, retinoblastoma, malignant peripheral nerve sheath tumor, infantile myofibromatosis, medulloblastoma SHH , rhabdoid tumor as well as atypical teratoid/rhabdoid tumor. Based on cancer type only, 12.1% of all children with cancer have an indication for a genetic evaluation. Pediatric oncology patients require access to genetic counselling and testing.

Choose and stay on one out of two paths: distinction between clinical versus research genetic testing to identify cancer predisposition syndromes among patients with cancer - Tim Ripperger; D Gareth Evans; David Malkin; Christian P. Kratz (Familial Cancer, 2021)

Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group - M. C. Frühwald; K. Nemes; H. Boztug; M. C. A. Cornips; D. G. Evans; R. Farah; S. Glentis; M. Jorgensen; K. Katsibardi; S. Hirsch; K. Jahnukainen; I. Kventsel; et al. (Familial Cancer, 2021)
The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group - Simone Hettmer; Guillaume Dachy; Guido Seitz; Abbas Agaimy; Catriona Duncan; Marjolijn Jongmans; Steffen Hirsch; Iris Kventsel; Uwe Kordes; Ronald R. de Krijger; Markus Metzler; Orli Michaeli; et al. (Familial Cancer, 2021)
Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/ PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

In memoriam Professor Thierry Frébourg - Gaëlle Bougeard (Familial Cancer, 2021)

Hereditary medullary thyroid carcinoma syndromes: experience from western India - Chakra Diwaker; Vijaya Sarathi; Sanjeet Kumar Jaiswal; Ravikumar Shah; Anuja Deshmukh; Anand Ebin Thomas; Gagan Prakash; Gaurav Malhotra; Virendra Patil; Anurag Lila; Nalini Shah; Tushar Bandgar (Familial Cancer, 2021)

Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting - Holly Carwana; Elizabeth Hoodfar; JoAnn Bergoffen; Dan Li (Familial Cancer, 2021)

Early-onset malignant phyllodes breast tumor in a patient with germline pathogenic variants in NF1 and BRCA1 genes - Francesca Gensini; Roberta Sestini; Alessandro De Luca; Valentina Pinna; Paola Daniele; Lorenzo Orzalesi; Maria Cristina Petrella; Berardino Porfirio; Laura Papi (Familial Cancer, 2021)

Age at diagnosis of cancer in 185delAG BRCA1 mutation carriers of diverse ethnicities: tentative evidence for modifier factors - Yael Laitman; Rachel Michaelson-Cohen; Rakefet Chen-Shtoyerman; Yael Goldberg; Orit Reish; Rinat Bernstein-Molho; Ephrat Levy-Lahad; Noa Ephrat Ben Baruch; Inbal Kedar; D. Gareth Evans; Sara Haim; Shani Paluch-Shimon; et al. (Familial Cancer, 2021)

Identification and management of Lynch syndrome in the Middle East and North African countries: outcome of a survey in 12 countries - Mohammad Sina; Zeinab Ghorbanoghli; Amal Abedrabbo; Fahd Al-Mulla; Rihab Ben Sghaier; Marie-Pierre Buisine; George Cortas; Ladan Goshayeshi; Andreas Hadjisavvas; Wail Hammoudeh; Waseem Hamoudi; Carol Jabari; et al. (Familial Cancer, 2021)
Background Lynch syndrome (LS), the most common inherited form of colorectal cancer (CRC), is responsible for 3% of all cases of CRC. LS is caused by a mismatch repair gene defect and is characterized by a high risk for CRC, endometrial cancer and several other cancers. Identification of LS is of utmost importance because colonoscopic surveillance substantially improves a patient’s prognosis. Recently, a network of physicians in Middle Eastern and North African (ME/NA) countries was established to improve the identification and management of LS families. The aim of the present survey was to evaluate current healthcare for families with LS in this region. Methods A questionnaire was developed that addressed the following issues: availability of clinical management guidelines for LS; attention paid to family history of cancer; availability of genetic services for identification and diagnosis of LS; and assessment of knowledge of LS surveillance. Members of the network and authors of recent papers on LS from ME/NA and neighbouring countries were invited to participate in the survey and complete the online questionnaire. Results A total of 55 individuals were invited and 19 respondents from twelve countries including Algeria, Azerbaijan, Cyprus, Egypt, Iran, Jordan, Kuwait, Lebanon, Morocco, Palestine, Tunisia, and Turkey completed the questionnaire. The results showed that family history of CRC is considered in less than half of the surveyed countries. Guidelines for the management of LS are available in three out of twelve countries. The identification and selection of families for genetic testing were based on clinical criteria (Amsterdam criteria II or Revised Bethesda criteria) in most countries, and only one country performed universal screening. In most of the surveyed countries genetic services were available in few hospitals or only in a research setting. However, surveillance of LS families was offered in the majority of countries and most frequently consisted of regular colonoscopy. Conclusion The identification and management of LS in ME/NA countries are suboptimal and as a result most LS families in the region remain undetected. Future efforts should focus on increasing awareness of LS amongst both the general population and doctors, and on the improvement of the infrastructure in these countries.

A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid carcinoma - Josep Oriola; Aurora Sanchez; Blanca Paniello; Jordi Puig de la Bellacasa; Josefina Biarnés (Familial Cancer, 2021)

Frequency and spectrum of mutations across 94 cancer predisposition genes in African American women with invasive breast cancer - Leann A. Lovejoy; Seth K. Rummel; Clesson E. Turner; Craig D. Shriver; Rachel E. Ellsworth (Familial Cancer, 2021)

The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer - Carla Escudeiro; Carla Pinto; Joana Vieira; Ana Peixoto; Pedro Pinto; Manuela Pinheiro; Catarina Santos; Joana Guerra; Susana Lisboa; Rui Santos; João Silva; Conceição Leal; et al. (Familial Cancer, 2021)

Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies - Monika Vyas; Canan Firat; Jaclyn F. Hechtman; Martin R. Weiser; Rona Yaeger; Chad Vanderbilt; Jamal K. Benhamida; Ajaratu Keshinro; Liying Zhang; Peter Ntiamoah; Marco Gonzalez; Rebecca Andrade; et al. (Familial Cancer, 2021)

FRAMe: Familial Risk Assessment of Melanoma—a risk prediction tool to guide CDKN2A germline mutation testing in Australian familial melanoma - Elizabeth A. Holland; Serigne Lo; Blake Kelly; Helen Schmid; Anne E. Cust; Jane M. Palmer; Martin Drummond; Nicholas K. Hayward; Antonia L. Pritchard; Graham J. Mann (Familial Cancer, 2021)

Correction to: Letter to the Editor—Recent advances in Lynch syndrome - Pål Møller; Julian Sampson; Mev Dominguez-Valentin; John Burn; Lone Sunde; Gabriela Möslein; Jukka-Pekka Mecklin; Toni Seppälä (Familial Cancer, 2021)

Correction to: Letter to the Editor—Recent advances in Lynch syndrome: response to Møller et al. - Leah H. Biller; Sapna Syngal; Matthew B. Yurgelun (Familial Cancer, 2021)

Patient reported experiences following laparoscopic prophylactic bilateral salpingo-oophorectomy or salpingectomy in an ambulatory care hospital - Rachel Trister; Michelle Jacobson; Patricia Nguyen; Mara Sobel; Lisa Allen; Steven A. Narod; Joanne Kotsopoulos (Familial Cancer, 2021)

Quantitative evaluation of MSI testing using NGS detects the imperceptible microsatellite changed caused by MSH6 deficiency - Gou Yamamoto; Takashi Takenoya; Akemi Takahashi; Yukiko Osanai; Miho Kakuta; Tetsuhiko Tachikawa; Takanori Washio; Masato Kamiyama; Michio Shiibashi; Shigeki Yamaguchi; Kiwamu Akagi (Familial Cancer, 2021)

Prevalence of pancreaticobiliary cancers in Irish families with pathogenic BRCA1 and BRCA2 variants - Robert Power; Cristin Leavy; Carmel Nolan; Niamh White; Roisin Clarke; Karen A. Cadoo; David James Gallagher; Maeve Aine Lowery (Familial Cancer, 2021)

Worldwide variation in lynch syndrome screening: case for universal screening in low colorectal cancer prevalence areas - George Kunnackal John; Vipin Das Villgran; Christine Caufield-Noll; Francis Giardiello (Familial Cancer, 2021)

Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer - Qiting Wan; Li Hu; Tao Ouyang; Jinfeng Li; Tianfeng Wang; Zhaoqing Fan; Tie Fan; Benyao Lin; Ye Xu; Yuntao Xie (Familial Cancer, 2021)

Letter to the Editor-Recent advances in Lynch syndrome - Pål Møller; Julian Sampson; Mev Dominguez-Valentin; John Burn; Lone Sunde; Gabriela Möslein; Jukka-Pekka Mecklin; Toni Seppälä (Familial Cancer, 2021)

Is a colorectal neoplasm diagnosis a trigger to change dietary and other lifestyle habits for persons with Lynch syndrome? A prospective cohort study - Jesca G. M. Brouwer; Merel Snellen; Tanya M. Bisseling; Jan Jacob Koornstra; Hans F. A. Vasen; Ellen Kampman; Fränzel J. B. van Duijnhoven (Familial Cancer, 2021)
A cancer diagnosis is suggested to be associated with changes in dietary and lifestyle habits. Whether this applies to persons with familial cancer, such as Lynch syndrome (LS) is unknown. We investigated whether a colorectal neoplasm (CRN) diagnosis in persons with LS is associated with changes in dietary and lifestyle habits over time. We used data of confirmed LS mutation carriers from the GEOLynch study, a prospective cohort study. Information on dietary intake and lifestyle habits was collected with a validated semi-quantitative food frequency questionnaire and a general questionnaire administered at baseline (2006–2008) and follow-up (2012–2017). Participants’ medical records were used to identify CRN diagnoses. Changes in dietary and lifestyle habits in the CRN and the no-CRN group were compared using multivariable linear regression models for continuous variables and cross-tables with percentage change at follow-up compared with baseline for categorical variables. Of the 324 included participants, 146 developed a CRN (CRN group) between baseline and follow-up, while 178 did not (no-CRN group). Smoking cessation was more often reported in the CRN than in the no-CRN group (41.4% vs. 35.0%). There were no differences in changes of energy intake, alcohol, red meat, processed meat, dairy, fruit, vegetables and dietary fiber consumption, BMI, physical activity and NSAID use. Apart from a potentially higher likelihood of smoking cessation, we found little evidence that a CRN diagnosis is associated with changes in lifestyle habits in persons with LS.

Barriers and facilitators to CDH1 carriers contemplating or undergoing prophylactic total gastrectomy - Kaitlin M. McGarragle; Tae L. Hart; Carol Swallow; Savtaj Brar; Anand Govindarajan; Zane Cohen; Melyssa Aronson (Familial Cancer, 2021)

Letter to the Editor-Recent advances in Lynch syndrome: response to Møller et al. - Leah H. Biller; Sapna Syngal; Matthew B. Yurgelun (Familial Cancer, 2021)

Characterizing germline APC and MUTYH variants in Ashkenazi Jews compared to other individuals - Chinedu Ukaegbu; Zohar Levi; Tara D. Fehlmann; Hajime Uno; Anu Chittenden; Jennifer A. Inra; Shilpa Grover; Fay Kastrinos; Sapna Syngal; Matthew B. Yurgelun (Familial Cancer, 2021)

The CAPP II trial of aspirin in Lynch syndrome/HNPCC: is it time for everyone to be treated? - Patrick M. Lynch (Familial Cancer, 2021)

New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer - D. Gareth Evans; Emma R. Woodward (Familial Cancer, 2021)

Multiple primary cancers (renal papillary, lymphoma and teratoma) and hepatic cysts in association with a pathogenic germline mutation in the MET gene - Julian Adlard (Familial Cancer, 2021)

Complete response of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated renal cell carcinoma to nivolumab and ipilimumab combination immunotherapy by: a case report - Yasuhiro Iribe; Mitsuko Furuya; Yousuke Shibata; Masato Yasui; Makoto Funahashi; Junichi Ota; Hiromichi Iwashita; Yoji Nagashima; Hisashi Hasumi; Narihiko Hayashi; Kazuhide Makiyama; Keiichi Kondo; et al. (Familial Cancer, 2021)

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019 - M. Suerink; K. Wimmer; L. Brugieres; C. Colas; R. Gallon; T. Ripperger; P. R. Benusiglio; E. M. A. Bleiker; Z. Ghorbanoghli; Y. Goldberg; J. C. H. Hardwick; M. Kloor; et al. (Familial Cancer, 2021)