scholarly journals Co‐occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome

2021 ◽  
Vol 41 (3) ◽  
pp. 218-228
Author(s):  
Rosario Ferrer‐Avargues ◽  
María Isabel Castillejo ◽  
Estela Dámaso ◽  
Virginia Díez‐Obrero ◽  
Noemí Garrigos ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Hereditary Cancer ◽  
Hereditary Cancer Syndromes ◽  
Pathogenic Variants ◽  
Cancer Syndromes

scholarly journals Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort

2022 ◽  
Vol 11 ◽  
Author(s):  
Van Thuan Tran ◽  
Sao Trung Nguyen ◽  
Xuan Dung Pham ◽  
Thanh Hai Phan ◽  
Van Chu Nguyen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Hereditary Cancer ◽  
Carrier Frequency ◽  
Hereditary Cancer Syndromes ◽  
Cancer Syndrome ◽  
Pathogenic Variants ◽  
History Of ◽  
Cancer Syndromes ◽  
History Of Cancer

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.

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

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Margaret Ward, DNP, APRN, AGNP-BC ◽  
Betty Elder, PhD, RN ◽  
Maryon Habtemariam, DNP, APRN
Keyword(s):  
Genetic Testing ◽  
Retrospective Analysis ◽  
Hereditary Cancer ◽  
Hereditary Cancer Syndrome ◽  
Hereditary Cancer Syndromes ◽  
Cancer Syndrome ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Preventative Measures ◽  
Cancer Syndromes

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.

Comprehensive next generation sequencing assay and bioinformatic pipeline for identifying pathogenic variants associated with hereditary cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13105-e13105
Author(s):  
Oscar Puig ◽  
Eugene Joseph ◽  
Malgorzata Jaremko ◽  
Gregory Kellogg ◽  
Robert Wisotzkey ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hereditary Cancer ◽  
Clinical Laboratory ◽  
Hereditary Cancer Syndromes ◽  
Hereditary Cancers ◽  
1000 Genomes ◽  
Pathogenic Variants ◽  
End To End ◽  
Cancer Syndromes ◽  
Generation Sequencing

e13105 Background: Diagnosis of hereditary cancer syndromes involves time-consuming comprehensive clinical and laboratory work-up, however, timely and accurate diagnosis is pivotal to the clinical management of cancer patients. Germline genetic testing has shown to facilitate the diagnostic process, allowing for identification and management of individuals at risk for inherited cancers. However, the laboratory diagnostics process requires not only development and validation of comprehensive gene panels to improve diagnostic yields, but a quality driven workflow including an end-to-end bioinformatics pipeline, and a robust process for variant classification. We will present a gene panel for the evaluation of hereditary cancer syndromes, conducted utilizing our novel end-to-end workflow, and validated in the CLIA-approved environment. Methods: A targeted Next-Generation Sequencing (NGS) panel consisting of 130 genes, including exons, promoters, 5’-UTRs, 3’-UTRs and selected introns, was designed to include genes associated with hereditary cancers. The assay was validated using samples from the 1000 genomes project and samples with known pathogenic variants. Elements software was utilized for end-to-end bioinformatic process ensuring adherence with the CLIA quality standards, and supporting manual curation of sequence variants. Results: Preliminary data from our current panel of genes associated with hereditary cancer syndromes revealed high sensitivity, specificity, and positive predictive value. Accuracy was confirmed by analysis of known SNVs, indels, and CNVs using 1000 Genomes and samples carrying pathogenic variants. The bioinformatics software allowed for an end-to-end quality controlled process of handling and analyzing of the NGS data, showing applicability for a clinical laboratory workflow. Conclusions: We have developed a comprehensive and accurate genetic testing process based on an automated and quality driven bioinformatics workflow that can be used to identify clinically important variants in genes associated with hereditary cancers. It's performance allows for implementation in the clinical laboratory setting.

scholarly journals Validation of a Digital Identification Tool for Individuals at Risk for Hereditary Cancer Syndromes

2018 ◽  
Author(s):  
Leslie Bucheit ◽  
Katherine Johansen Taber ◽  
Kaylene Ready
Keyword(s):  
At Risk ◽  
High Risk ◽  
Lynch Syndrome ◽  
Hereditary Cancer ◽  
Hereditary Cancer Syndromes ◽  
Independent Events ◽  
Digital Identification ◽  
Cancer Syndromes ◽  
Testing Criteria ◽  
Identification Tool

The number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria. Methods: Third-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI). Results: 197 pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04-100% CI) and specificity of 99.48% (98.13-99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06-99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS. Conclusions: The digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.

scholarly journals Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Amanda Ferreira Vidal ◽  
Rafaella Sousa Ferraz ◽  
Antonette El-Husny ◽  
Caio Santos Silva ◽  
Tatiana Vinasco-Sandoval ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Hereditary Cancer ◽  
Genetic Diagnosis ◽  
Hereditary Cancer Syndromes ◽  
Familial History ◽  
Pathogenic Variants ◽  
Individualized Care ◽  
Cancer Syndromes ◽  
Pan Cancer ◽  
Cancer Panel

Abstract Background Next generation sequencing (NGS) has been a handy tool in clinical practice, mainly due to its efficiency and cost-effectiveness. It has been widely used in genetic diagnosis of several inherited diseases, and, in clinical oncology, it may enhance the discovery of new susceptibility genes and enable individualized care of cancer patients. In this context, we explored a pan-cancer panel in the investigation of germline variants in Brazilian patients presenting clinical criteria for hereditary cancer syndromes or familial history. Methods Seventy-one individuals diagnosed or with familial history of hereditary cancer syndromes were submitted to custom pan-cancer panel including 16 high and moderate penetrance genes previously associated with hereditary cancer syndromes (APC, BRCA1, BRCA2, CDH1, CDKN2A, CHEK2, MSH2, MSH6, MUTYH, PTEN, RB1, RET, TP53, VHL, XPA and XPC). All pathogenic variants were validated by Sanger sequencing. Results We identified a total of eight pathogenic variants among 12 of 71 individuals (16.9%). Among the mutation-positive subjects, 50% were diagnosed with breast cancer and had mutations in BRCA1, CDH1 and MUTYH. Notably, 33.3% were individuals diagnosed with polyposis or who had family cases and harbored pathogenic mutations in APC and MUTYH. The remaining individuals (16.7%) were gastric cancer patients with pathogenic variants in CDH1 and MSH2. Overall, 54 (76.05%) individuals presented at least one variant uncertain significance (VUS), totalizing 81 VUS. Of these, seven were predicted to have disease-causing potential. Conclusion Overall, analysis of all these genes in NGS-panel allowed the identification not only of pathogenic variants related to hereditary cancer syndromes but also of some VUS that need further clinical and molecular investigations. The results obtained in this study had a significant impact on patients and their relatives since it allowed genetic counselling and personalized management decisions.

scholarly journals Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark

2021 ◽  
pp. 1103-1111
Author(s):  
Charles Muller ◽  
Sarah M. Nielsen ◽  
Kathryn E. Hatchell ◽  
Shan Yang ◽  
Scott T. Michalski ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lynch Syndrome ◽  
Hereditary Cancer ◽  
Medicare Beneficiaries ◽  
Cancer Genes ◽  
Hereditary Cancer Syndromes ◽  
Clinical Criteria ◽  
Cancer Syndromes ◽  
Testing Criteria ◽  
Variant Identification

PURPOSE Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.

scholarly journals Systemic Barriers to Risk-Reducing Interventions for Hereditary Cancer Syndromes: Implications for Health Care Inequities

2021 ◽  
pp. 1709-1718
Author(s):  
Kathleen F. Mittendorf ◽  
Sarah Knerr ◽  
Tia L. Kauffman ◽  
Nangel M. Lindberg ◽  
Katherine P. Anderson ◽  
...  
Keyword(s):  
Health Care ◽  
Hereditary Cancer ◽  
Hereditary Cancer Syndromes ◽  
Cancer Syndromes ◽  
Risk Reducing ◽  
Systemic Barriers

Hereditary cancer syndromes as model systems for chemopreventive agent development

2016 ◽  
Vol 43 (1) ◽  
pp. 134-145 ◽  
Author(s):  
Farzana L. Walcott ◽  
Jigar Patel ◽  
Ronald Lubet ◽  
Luz Rodriguez ◽  
Kathleen A. Calzone
Keyword(s):  
Hereditary Cancer ◽  
Model Systems ◽  
Hereditary Cancer Syndromes ◽  
Chemopreventive Agent ◽  
Cancer Syndromes ◽  
Agent Development
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