Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. We performed a genome-wide association analysis in the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10–6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14–1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

中文翻译：

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女性环境癌症和辐射流行病学研究中对侧乳腺癌的全基因组关联研究

对侧乳腺癌 (CBC) 是乳腺癌幸存者中最常见的第二原发癌症，但对 CBC 遗传易感性的了解，尤其是常见变异的了解仍然不完整。本研究旨在调查 CBC 的遗传基础，以更好地了解这种恶性肿瘤。我们在女性环境癌症和辐射流行病学 (WECARE) 研究中对年龄 < 55 岁首次诊断出乳腺癌的女性进行了全基因组关联分析，其中包括 1161 名 CBC 病例和 1668 名单侧乳腺癌 (UBC) 病例。作为对照。我们观察到两个基因座（rs59657211、9q32、SLC31A2/FAM225A 和 rs3815096、6p22.1、TRIM31）具有暗示全基因组显着关联（P < 1 × 10-6）。我们还发现 CBC 风险增加与乳腺癌特异性多基因风险评分 (PRS) 相关，该评分由 239 个已知乳腺癌易感性单核苷酸多态性 (SNP) 组成（每 1-SD 变化的比率：1.25；95% 置信区间 1.14 –1.36，P < 0.0001）。化疗对 CBC 风险的保护作用仅在 PRS 升高的患者中具有统计学意义（Pheterogenity = 0.04）。包括 PRS 和已知乳腺癌危险因素的 AUC 显着升高。目前的 GWAS 鉴定了两个先前未报告的具有暗示全基因组意义的位点。我们还证实，CBC 风险升高与综合乳腺癌易感性 PRS 相关，而 PRS 与已知的乳腺癌危险因素无关。这些发现增进了我们对 CBC 病因学中涉及的遗传风险因素的理解。