Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11–4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29–9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58–16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91–5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21–7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes. Significance: This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.

中文翻译：

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乳腺癌幸存者第二原发癌症的遗传风险：多种族队列研究


过去患有乳腺癌的女性患第二原发癌症 (SPC) 的风险增加，包括第二原发乳腺癌 (SPBC) 或第二原发非乳腺癌 (SPNBC)。在多种族队列 (MEC) 研究中，我们对来自 5 个种族/族裔群体（白人、非裔美国人、日裔美国人、拉丁裔和夏威夷原住民）的 3,223 名女性乳腺癌幸存者进行了前瞻性队列分析，以评估罕见致病变异的关联(PV) 存在于 37 个已知具有 SPC 风险的癌症易感基因中。共有 719 名（22.3%）女性患有 SPC，其中 323 名（10.0%）患有 SPBC。患有 SPC 的女性中，BRCA1（HR，2.28；95% CI，1.11–4.65）和 ERCC2（HR，3.51；95% CI，1.29–9.54）的种系 PV 显着丰富。在 SPBC 的亚型分析中，观察到 ERCC2 PV 的显着关联（HR，5.09；95% CI，1.58–16.4）和 BRCA2 PV 的暗示关联（HR，2.24；95% CI，0.91–5.55）。 BRCA1 PV 携带者发生 SPNBC 的风险也较高（HR，2.98；95% CI，1.21-7.36）。这些结果提供证据表明，BRCA1、BRCA2 和 ERCC2 中的种系 PV 有助于乳腺癌幸存者中 SPC 的发展。这些发现还表明，受损的 DNA 修复机制可能是乳腺癌患者 SPC 的易感因素，这支持需要对携带这些基因中的 PV 的女性进行更密切的 SPC 监测。意义：这项多种族研究将 BRCA1、BRCA2 和 ERCC2 的种系致病变异与乳腺癌幸存者第二原发癌的发展联系起来，提供生物学见解和生物标志物来指导患者监测。