Pathogenic Variants in Cancer Susceptibility Genes Predispose to Ductal Carcinoma In Situ of the Breast.
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Huang Huaizhi, Couch Ronan E, Karam Rachid, Hu Chunling, Boddicker Nicholas, Polley Eric C, Na Jie, Ambrosone Christine B, Yao Song, Trentham-Dietz Amy, Eliassen A Heather, Penney Kathryn, Brantley Kristen, Bodelon Clara, Teras Lauren R, Hodge James, Patel Alpa, Haiman Christopher A, John Esther M, Neuhausen Susan L, Martinez Elena, Lacey James V, O'Brien Katie M, Sandler Dale P, Weinberg Clarice R, Palmer Julie R, Bertrand Kimberly A, Vachon Celine M, Olson Janet E, Ruddy Kathryn E, Anton-Culver Hoda, Ziogas Argyrios, Goldgar David E, Nathanson Katherine L, Domchek Susan M, Weitzel Jeffrey N, Kraft Peter, Dolinsky Jill S, Pesaran Tina, Richardson Marcy E, Yadav Siddhartha, Couch Fergus J
Аннотация
EXPERIMENTAL DESIGN: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls and between DCIS and invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort.
RESULTS: Germline PV were observed in 6.5% and 4.6% of women with DCIS in the clinical testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PV frequencies were significantly lower among women with DCIS than those with IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PV were significantly associated with an increased risk of DCIS (OR > 2.0), but only BRCA2 PV were associated with high risk (OR > 4) in both cohorts. The cumulative incidence of CBC among carriers of PV in high-penetrance genes with DCIS was 23% over 15 years.
CONCLUSIONS: The enrichment of PV in ATM, BRCA1, BRCA2, CHEK2, and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of CBC in carriers of PV in high-penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.