Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.
Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.
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DOI：
10.1093/jnci/djw302
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发表时间：
2017-07-01
期刊：
影响因子：
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通讯作者：
Antoniou AC
中科院分区：
文献类型：
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作者：
Kuchenbaecker KB;McGuffog L;Barrowdale D;Lee A;Soucy P;Dennis J;Domchek SM;Robson M;Spurdle AB;Ramus SJ;Mavaddat N;Terry MB;Neuhausen SL;Schmutzler RK;Simard J;Pharoah PDP;Offit K;Couch FJ;Chenevix-Trench G;Easton DF;Antoniou AC
背景：全基因组关联研究（GWAS）已经确定了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snp。其中一些也与携带高危BC和OC基因BRCA1或BRCA2致病性突变的女性患BC或OC的风险有关。这些变异对BRCA1和BRCA2突变携带者的BC或OC风险的综合影响尚未得到评估，但他们的临床管理可能受益于改进的个性化风险评估。方法：我们利用基于人群的GWAS鉴定的BC和OC易感性snp构建了多基因风险评分（PRS）： BC（总体而言，雌激素受体[ER]阳性和ER阴性）和OC。使用来自15252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PRS每标准差增加的风险比（hr）。结果：er阴性BC的PRS与BRCA1携带者的BC风险相关性最强（HR = 1.27, 95%可信区间[CI] = 1.23 ~ 1.31, P = 8.2×10−53）。在BRCA2携带者中，总体BC PRS与BC风险的相关性最强（HR = 1.22, 95% CI = 1.17至1.28,P = 7.2×10−20）。在BRCA1和BRCA2携带者中，OC PRS与OC风险密切相关。这些转化为PRS分布的最高和最低十分位数之间的绝对风险差异（每种情况下都超过10%）；例如，在80岁时，在第10百分位的BRCA2携带者患卵巢癌的风险为6%，而在第90百分位的BRCA2携带者患卵巢癌的风险为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。
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.