Background Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P =  8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P =  7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

中文翻译：

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BRCA1 和 BRCA2 突变携带者乳腺癌和卵巢癌风险预测的多基因风险评分评估。

背景 全基因组关联研究 (GWAS) 已确定 94 个与乳腺癌 (BC) 风险相关的常见单核苷酸多态性 (SNP) 和 18 个与卵巢癌 (OC) 风险相关的常见单核苷酸多态性 (SNP)。对于携带高危 BC 和 OC 基因 BRCA1 或 BRCA2 致病性突变的女性，其中一些因素还与 BC 或 OC 的风险相关。这些变异对 BRCA1 和 BRCA2 突变携带者 BC 或 OC 风险的综合影响尚未评估，而其临床管理可能会受益于改进的个性化风险估计。方法 我们使用通过基于人群的 GWAS 确定的 BC 和 OC 易感性 SNP 构建了多基因风险评分 (PRS)：对于 BC（总体而言，雌激素受体 [ER] 阳性和 ER 阴性）和 OC。使用 15 252 名女性 BRCA1 和 8211 名 BRCA2 携带者的数据，使用加权队列方法评估每种 PRS 与 BC 或 OC 风险的关联，以诊断时间作为结果，并估计每个标准差增加的风险比 (HR)在 PRS 中。结果 ER 阴性 BC 的 PRS 与 BRCA1 携带者的 BC 风险关联性最强（HR = 1.27，95% 置信区间 [CI] = 1.23 至 1.31，P = 8.2×10 -53 ）。在 BRCA2 携带者中，总体 BC PRS 与 BC 风险的关联性最强（HR = 1.22，95% CI = 1.17 至 1.28，P = 7.2×10 -20 ）。对于 BRCA1 和 BRCA2 携带者来说，OC PRS 与 OC 风险密切相关。这些转化为 PRS 分布顶部和底部十分位数之间绝对风险的差异（每种情况均超过 10%）；例如，对于 OC PRS 第 10 个百分位数的 BRCA2 携带者来说，到 80 岁时，OC 风险为 6%，而 PRS 第 90 个百分位数的 BRCA2 携带者的 OC 风险为 19%。结论 BC 和 OC PRS 可预测 BRCA1 和 BRCA2 携带者的癌症风险。将 PRS 纳入风险预测模型有望更好地为癌症风险管理决策提供信息。