Harvard T.H. Chan School of Public Health, Boston, MA.
Mayo Clinic, Rochester, MN.
J Clin Oncol. 2021 Aug 10;39(23):2564-2573. doi: 10.1200/JCO.20.01992. Epub 2021 Jun 8.
This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population.
A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in , , , , , , , , and . PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC.
The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of , , and carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of and carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk.
PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of and nearly half of carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.
本研究评估了乳腺癌（BC）易感基因中的致病性变异（PVs）和多基因风险评分（PRS）与普通人群中 BC 的联合关联。
在癌症风险估计相关易感性联盟中，共有 26798 例非西班牙裔白人 BC 病例和 26127 例对照来自主要基于人群的研究，评估了 、 、 、 、 、 、 和 中 PVs 的情况。基于 105 个常见变异的 PRS 是使用来自 BC 全基因组关联研究的效应估计值创建的；评估了整体 BC PRS 和雌激素受体特异性 PRS 的性能。使用 penalized logistic regression 估计基于 PV 和 PRS 的 BC 发生几率。将结果与年龄特异性发病率相结合，以估计按 PV 状态和一级亲属 BC 家族史划分的 PRS 百分位数的 BC 5 年和终生绝对风险。
在普通人群非携带者中，基于 PRS 的第 10 和第 90 百分位数，一级亲属中无或有 BC 的女性的 BC 终生风险估计分别为 9.1%-23.9%和 6.7%-18.2%。考虑到 PRS，超过 95%的 、 、 和 携带者的 BC 终生风险>20%，而一级亲属中无 BC 的 、 和 携带者分别有 52.5%和 69.7%、一级亲属中有 BC 的携带者分别有 78.8%和 89.9%的风险>20%。
PRS 有助于对易感基因中 PVs 携带者的 BC 风险进行个体化。将 PRS 纳入 BC 风险评估中可能有助于识别>30%的 、 携带者和近一半的一级亲属中无 BC 的 携带者，其风险>20%，这表明添加 PRS 可能有助于避免过度筛查，并实现更个性化的风险管理方法。
