Clinical outcomes of preimplantation genetic testing for hereditary cancer syndromes: A systematic review

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.

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High Oncotype Recurrence Score, Hereditary Cancer Syndromes, and Referral for Genetic Testing

Clinical Breast Cancer ◽

10.1016/j.clbc.2019.09.006 ◽

2020 ◽

Vol 20 (2) ◽

pp. e196-e197

Author(s):

Arun Kumar Goel ◽

Vaishali Zamre ◽

Prekshi Chaudhary ◽

Gopal Sharma ◽

Dinesh Singh

Keyword(s):

Genetic Testing ◽

Hereditary Cancer ◽

Recurrence Score ◽

Hereditary Cancer Syndromes ◽

Cancer Syndromes

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PTEN Germline Mutations in Patients Initially Tested for Other Hereditary Cancer Syndromes: Would Use of Risk Assessment Tools Reduce Genetic Testing?

The Oncologist ◽

10.1634/theoncologist.2013-0174 ◽

2013 ◽

Vol 18 (10) ◽

pp. 1083-1090 ◽

Cited By ~ 17

Author(s):

Jessica L. Mester ◽

Rebekah A. Moore ◽

Charis Eng

Keyword(s):

Risk Assessment ◽

Genetic Testing ◽

Hereditary Cancer ◽

Germline Mutations ◽

Assessment Tools ◽

Hereditary Cancer Syndromes ◽

Risk Assessment Tools ◽

Cancer Syndromes

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The Perils of Single‐Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next‐Generation Sequencing

The Oncologist ◽

10.1634/theoncologist.2017-0372 ◽

2018 ◽

Vol 23 (4) ◽

pp. 393-396

Author(s):

Nicole Casasanta ◽

Elizabeth Stark ◽

Allison McHenry ◽

Tara Biagi ◽

Rebecca Kaltman

Keyword(s):

Genetic Testing ◽

Next Generation Sequencing ◽

Hereditary Cancer ◽

Single Site ◽

Next Generation ◽

Hereditary Cancer Syndromes ◽

Cancer Syndromes ◽

Generation Sequencing

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The dermatopathologist's role in genetic testing for hereditary cancer syndromes: Utility versus patient liberty

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2015.12.046 ◽

2016 ◽

Vol 74 (6) ◽

pp. 1282-1285 ◽

Cited By ~ 1

Author(s):

Stephanie K. Fabbro ◽

Benjamin K. Stoff

Keyword(s):

Genetic Testing ◽

Hereditary Cancer ◽

Hereditary Cancer Syndromes ◽

Cancer Syndromes

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

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.7.3 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13105 ◽

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.

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