Exome Sequencing–Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants

Autor: Kandamurugu Manickam, Miranda L.G. Hallquist, Heather Mason-Suares, Daniel R. Lavage, W. Andrew Faucett, Rosemary Leeming, Janet L. Williams, Adam H. Buchanan, Lacy E. Lowry, Sarath B Krishnamurthy, David J. Carey, David H. Ledbetter, Aris Baras, Frederick E. Dewey, Raghu Metpally, Amanda L. Lazzeri, Marc S. Williams, Juliann M. Savatt, Marylyn D. Ritchie, Noura S. Abul-Husn, Korey A. Kost, T. Nate Person, Monica A. Giovanni, Derick Hoskinson, Matthew S. Lebo, Marci L.B. Schwartz, Dustin N. Hartzel, Heather Rocha, Alanna Kulchak Rahm, Amy C. Sturm, Michael F. Murray, Jeffrey G. Reid, Cara Zayac McCormick, Carroll N. Flansburg, Alyson E. Evans, D’Andra M. Lindbuchler, Anne E. Justice, Victor G. Vogel, H. Lester Kirchner, Joseph B. Leader, Huntington F. Willard, John D. Overton, Lauren R. Frisbie, Loren Butry
Rok vydání: 2018
Předmět:
Zdroj: JAMA Network Open
ISSN: 2574-3805
Popis: Key Points Question Can population-level genomic screening identify those at risk for disease? Findings In this cross-sectional study of an unselected population cohort of 50 726 adults who underwent exome sequencing, pathogenic and likely pathogenic BRCA1 and BRCA2 variants were found in a higher proportion of patients than was previously reported. Meaning Current methods to identify BRCA1/2 variant carriers may not be sufficient as a screening tool; population genomic screening for hereditary breast and ovarian cancer may better identify patients at high risk and provide an intervention opportunity to reduce mortality and morbidity.
Importance Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. Objectives To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants. Design, Setting, and Participants This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in BRCA1/2. Main Outcomes Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers. Results Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13; P
This cross-sectional study investigates the ascertainment of pathogenic and likely pathogenic BRCA1/2 variants among US adults enrolled in the MyCode Community Health Initiative.
Databáze: OpenAIRE
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