Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort

BackgroundHereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.Methods1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.ResultsA total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.ConclusionThis is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.

The use of heuristics in genetic testing decision-making: A qualitative interview study

Background Decision-making concerning predictive genetic testing for hereditary cancer syndromes is inherently complex. This study aims to investigate what kind of complexities adults undergoing genetic counseling in Switzerland experience, how they deal with them, and what heuristics they use during the decision-making process. Methods Semi-structured qualitative interviews with eighteen Swiss adults seeking genetic counseling for hereditary cancer syndrome genetic testing and two counseling physicians were conducted and analyzed using a grounded theory approach. Results Counselees stated that once they were aware of their eligibility for genetic testing they perceived an inevitable necessity to make a decision in a context of uncertainties. Some counselees perceived this decision as simple, others as very complex. High emotional involvement increased perceived complexity. We observed six heuristics that counselees used to facilitate their decision: Anticipating the test result; Focusing on consequences; Dealing with information; Interpreting disease risk; Using external guidance; and (Re-)Considering the general uncertainty of life. Limitations Our findings are limited to the context of predictive genetic testing for hereditary cancer syndromes. This qualitative study does not allow extrapolation of the relative frequency of which heuristics occur. Conclusions The use of heuristics is an inherent part of decision-making, particularly in the complex context of genetic testing for inherited cancer predisposition. However, some heuristics increase the risk of misinterpretation or exaggerated external influences. This may negatively impact informed decision-making. Thus, this study illustrates the importance of genetic counselors and medical professionals being aware of these heuristics and the individual manner in which they might be applied in the context of genetic testing decision-making. Findings may offer practical support to achieve this, as they inductively focus on the counselees’ perspective.

Current Testing Guidelines: A Retrospective Analysis of a Community-Based Hereditary Cancer Program

It is estimated that 5% to 10% of all cancers are related to a hereditary cancer syndrome. However, specific cancers, such as pancreatic and ovarian cancers, are related to hereditary cancer syndromes 15% to 20% of the time. Genetic testing guidelines for hereditary cancer syndromes are frequently reviewed and updated by the National Comprehensive Cancer Network (NCCN). The purpose of this retrospective analysis is to identify carriers of pathogenic variants or hereditary cancer syndrome who do not meet NCCN criteria for testing and compare the results with previous studies. The data obtained can be used to provide recommendations to assess current guidelines for testing and evaluate the benefit of comprehensive panel testing vs. standard testing for specific hereditary cancer syndromes. This project is a retrospective review of clinical histories of patients who had multigene panel testing between September 2015 and February 2019 through a cancer outreach and risk assessment (CORA) program. Frequencies analyses were performed to analyze results. A total of 233 individuals were included in the analysis: 171 met BRCA1/2 testing criteria, 66 met Lynch syndrome criteria, and 4 met polyposis criteria. Of the individuals meeting established criteria for testing, 39 were identified with pathogenic variants. However, only 10 of these individuals were identified with a pathogenic variant associated with the criteria for which they met. Genetic testing that is limited to only those patients with genes associated with hereditary cancer syndromes may lead to exclusion of other potentially actionable genes, which may impair a patient’s ability to receive additional screening or preventative measures.

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches.