{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:08:13Z","timestamp":1786975693573,"version":"build-2736575974"},"reference-count":23,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This case-control study included CBC cases and matched unilateral breast cancer controls from The Women\u2019s Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study. Eligible women were diagnosed between 1985 and 2000 with data and biospecimens collected from 2001 to 2004. Eligible participants were women younger than 55 years at first invasive breast cancer diagnosis. Participants were matched on age, diagnosis year, cancer registry region, and race and ethnicity, and countermatched on radiation treatment. For cases, CBC occurred 1 year or more following first breast cancer diagnosis. Analyses were performed from May to October 2024.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n CHEK2<\/jats:italic>\n 1100delC and deleterious variants in\n ATM<\/jats:italic>\n ,\n BRCA1,<\/jats:italic>\n and\n BRCA2<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcome and Measure<\/jats:title>\n Development of CBC, measured as a rate ratio (RR).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 1290 women were included in analysis (median [IQR] age at first diagnosis, 47 [42-51] years). The ER-positive CBC rate for women with deleterious\n ATM<\/jats:italic>\n variants was 4 times higher than for women without deleterious\n ATM<\/jats:italic>\n variants (RR, 4.84; 95% CI, 1.11-21.08;\n P<\/jats:italic>\n \u2009=\u2009.04); no women with ER-negative CBC carried deleterious\n ATM<\/jats:italic>\n variants. The ER-positive CBC rates for women with deleterious variants in\n BRCA2<\/jats:italic>\n or\n CHEK2<\/jats:italic>\n 1100delC were 5 to 6 times higher than for women without deleterious variants in\n BRCA2<\/jats:italic>\n or\n CHEK2<\/jats:italic>\n 1100delC, respectively (\n BRCA2<\/jats:italic>\n : RR, 5.88; 95% CI, 2.61-13.26,\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001;\n CHEK2<\/jats:italic>\n 1100delC: RR, 6.06; 95% CI, 1.26-29.04;\n P<\/jats:italic>\n \u2009=\u2009.02). The ER-negative CBC rate for women with deleterious\n BRCA1<\/jats:italic>\n variants was 26 times higher than for women without deleterious\n BRCA1<\/jats:italic>\n variants (RR, 26.16; 95% CI, 8.01-85.44;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). First primary breast cancer ER status did not modify associations between deleterious variants and ER-specific CBC development.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this case-control study of CBC, deleterious variants in breast cancer susceptibility genes were differentially associated with ER-specific CBC development. Germline variation profile may inform estimates of outcomes for ER-specific CBC subtypes.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.52158","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T11:31:59Z","timestamp":1735558319000},"page":"e2452158","source":"Crossref","is-referenced-by-count":7,"title":["Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer"],"prefix":"10.1001","volume":"7","author":[{"given":"Anne S.","family":"Reiner","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon P.","family":"Watt","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New 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Research Institute, Sinai Health, Toronto, Ontario, Canada"},{"name":"Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Woods","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Tischkowitz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United 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