Abstract PD3-01: Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study
Authors: Couch Fergus J , Hu Chunling , Hart Steven N , Gnanaolivu Rohan , Lee Kun Y , Na Jie , Gao Chi , Boddicker Nicholas J , Eckloff Bruce , Samara Raed , Klebba Josh , Ambrosone Christine B , Anton-Culver Hoda , Auer Paul , Bernstein Leslie , Gaudet Mia M , Haiman Christopher , John Esther M , Neuhausen Susan , Olson Janet E , Pal Tuya , Palmer Julie R , Sandler Dale P , Taylor Jack A , Trentham-Dietz Amy , Vachon Celine M , Weinberg Clarice , Yao Song , Weitzel Jeffrey N , Goldgar David E , Domchek Susan M , Nathanson Katherine L , Kraft Peter , Polley Eric C 
Published: March 2020

Germline mutations in several cancer predisposition genes included in hereditary multigene testing panels have been associated with increased breast cancer risk. However, estimates of breast cancer risks for each gene have in large part been derived from studies of high-risk populations enriched for family history of breast and ovarian cancer, young age of breast cancer diagnosis, or founder mutations. The breast cancer risks associated with mutations in many of these genes in the general population remain to be clearly defined. As clinical hereditary cancer genetic testing is already provided to many women at increased risk and may soon be offered to all breast cancer patients, population-based risk estimates associated with predisposition gene mutations will be needed for appropriate clinical management of mutation carriers. The “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium of 17 cohort-based case-control, population-based case-control, and family studies focused on estimation of population-based breast cancer risks and penetrance analysis for mutations in known and candidate breast cancer predisposition genes. Germline DNA from 39486 breast cancer cases and 35868 matched controls was subjected to dual bar-coded QIAseq multiplex amplification of 1733 target regions in 37 predisposition genes. Products from sets of 768 samples were pooled and sequenced in each lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Verdict. High quality sequence data was obtained for 99.3% of target regions. Here we report on results from 34741 population-based breast cancer cases and 32728 matched unaffected controls. The mean age of breast cancer diagnosis for cases was 61.2 years and mean age for controls was 61.1 years. Overall, 20.9% of cases and 14.3% of controls had a family history of breast cancer. Furthermore, 74.3% of cases and 75.8% of controls were non-Hispanic white, whereas 13.3% of cases and 15.3% of controls were African American. Among cases with tumor information available, 81.7% were ER-positive and 7.7% were triple negative breast cancers (TNBC). We assessed mutation frequencies in 24 genes including 12 established breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, andTP53). The overall mutation frequency was 6.2% in cases and 2.7% in controls. Case-control association analysis after adjusting for study, age, family history of breast cancer, and race/ethnicity showed that BRCA1(OR=7.45; 95%CI:5.24-10.95) and BRCA2(OR=5.31; 95%CI:4.15-6.88) were associated with high risks of breast cancer in the general population. However, PALB2mutations were only associated with moderate risks (OR=3.63; 95%CI:2.57-5.26). ATMmutations conferred attenuated risks (OR=1.83; 95%CI:1.47-2.28) relative to studies of high-risk families or young onset breast cancers. NBNmutations were not associated with increased breast cancer risk. Mutations in BARD1, RAD51C, RAD51Dand XRCC2were specifically significantly associated with moderate risks of ER-negative breast cancer and TNBC, whereas mutations in ATM, CDH1and CHEK2were specifically significantly associated with ER-positive disease. On the basis of these findings age-related absolute breast cancer risks for commonly mutated genes were estimated. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in enriched populations including high-risk families and young onset, bilateral, or multiple primary cases. We anticipate that the results from this study will inform cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes.

Citation Format: Fergus J Couch, Chunling Hu, Steven N Hart, Rohan Gnanaolivu, Kun Y Lee, Jie Na, Chi Gao, Nicholas J Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Christine B Ambrosone, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia M Gaudet, Christopher Haiman, Esther M John, Susan Neuhausen, Janet E Olson, Tuya Pal, Julie R Palmer, Dale P Sandler, Jack A Taylor, Amy Trentham-Dietz, Celine M Vachon, Clarice Weinberg, Song Yao, Jeffrey N Weitzel, David E Goldgar, Susan M Domchek, Katherine L Nathanson, Peter Kraft, Eric C Polley. Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-01.