Association of Gene Variant Type and Location with Breast Cancer Risk in the General Population
Authors: Akamandisa Mwangala P. , Boddicker Nicholas J. , Yadav Siddhartha , Hu Chunling , Hart Steven N. , Ambrosone Christine , Anton-Culver Hoda , Auer Paul L. , Bodelon Clara , Burnside Elizabeth S. , Chen Fei , Eliassen Heather A. , Goldgar David E. , Haiman Christopher , Hodge James M. , Huang Hongyan , John Esther M. , Karam Rachid , Lacey James V. , Lindstroem Sara , Martinez Elana , Na Jie , Neuhausen Susan L. , O’Brien Katie M. , Olson Janet E. , Pal Tuya , Palmer Julie R. , Patel Alpa V. , Pesaran Tina , Polley Eric C. , Richardson Marcy E. , Ruddy Kathryn , Sandler Dale P. , Teras Lauren R. , Trentham-Dietz Amy , Vachon Celine M. , Weinberg Clarice , Winham Stacey J. , Yao Song , Zirpoli Gary , Kraft Peter , Weitzel Jeffrey N. , Domchek Susan M. , Couch Fergus J. , Nathanson Katherine L. 
Published: October 2024

AbstractImportancePathogenic variants (PVs) inATM, BRCA1, BRCA2, CHEK2, andPALB2are associated with increased breast cancer risk. However, it is unknown whether breast cancer risk differs by PV type or location in carriers ascertained from the general population.ObjectiveTo evaluate breast cancer risks associated with PV type and location inATM, BRCA1, BRCA2, CHEK2, andPALB2.DesignAge adjusted case-control association analysis for all participants, subsets of PV carriers, and women with no breast cancer family history in population-based and clinical testing cohorts.SettingTwelve US population-based studies within the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium, and breast cancer cases from the UK-Biobank and an Ambry Genetics clinical testing cohort.Participants32,247 women with and 32,544 age-matched women without a breast cancer diagnosis from CARRIERS; 237 and 1351 women withBRCA2PVs and breast cancer from the UKBB and Ambry Genetics, respectively.Exposure(s)PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2.Main Outcome(s) and Measure(s)PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and p-values) using logistic regression. Mean ages at diagnosis were compared using linear regression.ResultsCompared to women carryingBRCA2exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women withBRCA2ex13-27 PTVs (OR=2.7, 95%CI 1.1-7.9) and ex1-10 PTVs (OR=1.6, 95%CI 0.8-3.5) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9; ex1-10 OR=0.5, 95%CI 0.1-1.0), and earlier age of breast cancer diagnosis (ex13-27 5.5 years, p<0.001; ex1-10 2.4 years, p=0.17). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort and the population-based UK Biobank cohort. No differences in risk or age at diagnosis by gene region were observed for PTVs in other predisposition genes.Conclusions and RelevancePopulation-based and clinical high-risk cohorts establish that PTVs in exon 11 ofBRCA2are associated with reduced risk of breast cancer, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carryingBRCA2PTVs.Key PointsQuestionDoesATM,BRCA1,BRCA2,CHEK2andPALB2pathogenic variant type and location influence breast cancer risk in population-based studies?FindingsBreast cancer risk and estrogen receptor status differ based on the type and location of pathogenic variants inBRCA2. Women carrying protein truncating variants in exon 11 have a lower breast cancer risk in the population-based cohorts, older age at diagnosis and higher rates of estrogen receptor negative breast cancer than women with exon 1-10 or exon 13-27 truncation variants in population-based and clinical testing cohorts.MeaningIncorporating pathogenic variant type and location in cancer risk models may improve individualized risk prediction.