PDF(Pubmed)
Abstract：
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.
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.
摘要：
背景：对侧乳腺癌（CBC）是乳腺癌幸存者中最常见的第二原发癌，然而，对CBC遗传易感性的理解，特别是对于常见的变体，仍然不完整。本研究旨在探讨CBC的遗传基础，以更好地了解这种恶性肿瘤。
结果：我们在妇女环境癌症和放射流行病学（WECARE）研究中进行了全基因组关联分析，研究对象为年龄<55岁的首次诊断为乳腺癌的女性，包括1161例CBC和1668例单侧乳腺癌（UBC）作为对照。我们观察到两个基因座（rs59657211，9q32，SLC31A2/FAM225A和rs3815096，6p22.1，TRIM31），提示全基因组显着关联（P<1×10-6）。我们还发现与乳腺癌特异性多基因风险评分（PRS）相关的CBC风险增加，该评分包含239个已知的乳腺癌易感性单核苷酸多态性（SNP）（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（P异质性=0.04）。包括PRS和已知乳腺癌危险因素的AUC显著升高。
结论：目前的GWAS鉴定了两个以前未报告的基因座，具有全基因组意义。我们还证实，CBC风险升高与独立于已知乳腺癌风险因素的全面乳腺癌易感性PRS相关。这些发现促进了我们对涉及CBC病因的遗传风险因素的理解。
结果：我们在妇女环境癌症和放射流行病学（WECARE）研究中进行了全基因组关联分析，研究对象为年龄<55岁的首次诊断为乳腺癌的女性，包括1161例CBC和1668例单侧乳腺癌（UBC）作为对照。我们观察到两个基因座（rs59657211，9q32，SLC31A2/FAM225A和rs3815096，6p22.1，TRIM31），提示全基因组显着关联（P<1×10-6）。我们还发现与乳腺癌特异性多基因风险评分（PRS）相关的CBC风险增加，该评分包含239个已知的乳腺癌易感性单核苷酸多态性（SNP）（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（P异质性=0.04）。包括PRS和已知乳腺癌危险因素的AUC显著升高。
结论：目前的GWAS鉴定了两个以前未报告的基因座，具有全基因组意义。我们还证实，CBC风险升高与独立于已知乳腺癌风险因素的全面乳腺癌易感性PRS相关。这些发现促进了我们对涉及CBC病因的遗传风险因素的理解。
