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Weitzel JN , Kidd J , Bernhisel R , Shehayeb S , Frankel P , Blazer KR , Turco D , Nehoray B , McGreevy K , Svirsky K , Brown K , Gardiner A , Daly M , Hughes E , Cummings S , Saam J , Slavin TP
Multigene assessment of genetic risk for women for two or more breast cancers
Breast Cancer Res Treat. 2021 Apr 7;188(3) :759-768
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PURPOSE: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown. METHODS: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013 and 2018. Clinical data were obtained from provider-completed test request forms. For each gene on the panel, a multivariable logistic regression model was constructed to test for association with risk of multiple breast cancer diagnoses. Models accounted for age of diagnosis, personal and family cancer history, and ancestry. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: This study included 98,979 patients: 88,759 (89.7%) with a single breast cancer and 10,220 (10.3%) with ≥ 2 breast cancers. Of women with two or more breast cancers, 13.2% had a pathogenic variant in a cancer predisposition gene compared to 9.4% with a single breast cancer. BRCA1, BRCA2, CDH1, CHEK2, MSH6, PALB2, PTEN, and TP53 were significantly associated with two or more breast cancers, with ORs ranging from 1.35 for CHEK2 to 3.80 for PTEN. Overall, pathogenic variants in all breast cancer risk genes combined were associated with both metachronous (OR 1.65, 95% CI 1.53-1.79, p = 7.2 × 10(-33)) and synchronous (OR 1.33, 95% CI 1.19-1.50, p = 2.4 × 10(-6)) breast cancers. CONCLUSIONS: This study demonstrated that several high and moderate penetrance breast cancer susceptibility genes are associated with ≥ 2 breast cancers, affirming the association of two or more breast cancers with diverse genetic etiologies.
1573-7217 Weitzel, Jeffrey N Orcid: 0000-0001-6714-092x Kidd, John Bernhisel, Ryan Shehayeb, Susan Frankel, Paul Blazer, Kathleen R Turco, Diana Nehoray, Bita McGreevy, Kim Svirsky, Kira Brown, Krystal Gardiner, Anna Daly, Mary Hughes, Elisha Cummings, Shelly Saam, Jennifer Slavin, Thomas P R01CA242218/CA/NCI NIH HHS/United States K08CA234394/CA/NCI NIH HHS/United States P30CA033572/NH/NIH HHS/United States Research Professorship in Breast Cancer Diaparities/Conquer Cancer Foundation/ Journal Article Netherlands Breast Cancer Res Treat. 2021 Apr 7. doi: 10.1007/s10549-021-06201-y.