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. 2018 Sep 7;1(5):e182140.
doi: 10.1001/jamanetworkopen.2018.2140.

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

Kandamurugu Manickam  1   2 , Adam H Buchanan  2 , Marci L B Schwartz  2 , Miranda L G Hallquist  2 , Janet L Williams  2 , Alanna Kulchak Rahm  2 , Heather Rocha  2 , Juliann M Savatt  2 , Alyson E Evans  2 , Loren M Butry  2 , Amanda L Lazzeri  2 , D'Andra M Lindbuchler  2 , Carroll N Flansburg  2 , Rosemary Leeming  2 , Victor G Vogel  2 , Matthew S Lebo  3 , Heather M Mason-Suares  3 , Derick C Hoskinson  3 , Noura S Abul-Husn  4 , Frederick E Dewey  4 , John D Overton  4 , Jeffrey G Reid  4 , Aris Baras  4 , Huntington F Willard  2 , Cara Z McCormick  2 , Sarath B Krishnamurthy  2 , Dustin N Hartzel  2 , Korey A Kost  2 , Daniel R Lavage  2 , Amy C Sturm  2 , Lauren R Frisbie  2 , T Nate Person  2 , Raghu P Metpally  2 , Monica A Giovanni  2 , Lacy E Lowry  2 , Joseph B Leader  2 , Marylyn D Ritchie  2   5 , David J Carey  2 , Anne E Justice  2 , H Lester Kirchner  2 , W Andrew Faucett  2 , Marc S Williams  2 , David H Ledbetter  2 , Michael F Murray  2   6
Affiliations

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

Kandamurugu Manickam et al. JAMA Netw Open. .

Abstract

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 < .001). Ovarian cancer history was present in 15 (10.1%) of 148 variant carriers and in 195 (0.6%) of 29 880 variant noncarriers (OR, 18.30; 95% CI, 10.48-31.4; P < .001). Among 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing.

Conclusions and relevance: This study found that compared with previous clinical care, exome sequencing-based screening identified 5 times as many individuals with P/LP BRCA1/2 variants. These findings suggest that genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms J. L. Williams reported receiving grants from the National Human Genome Research Institute (NHGRI) during the conduct of the study. Dr Rahm reported receiving grants from NHGRI and from Regeneron Pharmaceuticals during the conduct of the study. Ms Flansburg reported receiving grants from Regeneron Genetics Center during the conduct of the study. Dr Vogel reported receiving grants from Regeneron Pharmaceuticals during the conduct of the study. Dr Lebo reported receiving grants from the National Institutes of Health (NIH)/NHGRI during the conduct of the study. Dr Baras reported being an employee of Regeneron Genetics Center outside of the submitted work. Mr Hartzel reported receiving compensation as an analyst through funding received by Geisinger from Regeneron Pharmaceuticals. Mr Lavage reported receiving compensation as an analyst through funding received by Geisinger from Regeneron Pharmaceuticals. Dr Ritchie reported receiving grants from Regeneron Genetics Center during the conduct of the study. Dr Kirchner reported receiving grants from Regeneron Pharmaceuticals during the conduct of the study. Mr Faucett reported receiving grants from NIH during the conduct of the study. Dr Ledbetter reported receiving grants from Regeneron Biopharmaceuticals during the conduct of the study. Dr Murray reported receiving grants from Regeneron Pharmaceuticals during the conduct of the study as well as personal fees from Invitae outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Eligibility for Return of Results
Of the 267 BRCA1/2 carriers, 183 (68.5%) received the clinically confirmed result through an electronic health record portal and were offered clinical risk management. In total, 84 participants withdrew from the study, died, or did not update their consent; these cases had only deidentified records and were not eligible for returned results.
Figure 2.
Figure 2.. Association of Pathogenic and Likely Pathogenic BRCA1/2 Variants With Relevant Syndromic Cancers
A, Relevant cancers in this analysis included breast, ovarian, prostate, pancreatic, and melanoma. BRCA1/2 controls included individuals without pathogenic and likely pathogenic BRCA1/2 variants. BRCA1/2 cases included BRCA1/2 carriers. Health system patients also included those who did not undergo screening. Mantel-Haenszel test was used to determine the fixed-effects odds ratio.
See this image and copyright information in PMC

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