METHODS: Using publicly available summary statistics of female breast cancer genome-wide association study (GWAS) of Japanese and European ancestries, we, respectively, developed 31 candidate genome-wide PRSs using pruning and thresholding (P + T) and LDpred methods with varying parameters. Among the candidate PRS models, the best model was selected using a case-cohort dataset (63 breast cancer cases and 2213 sub-cohorts of Japanese females during a median follow-up of 11.9 years) according to the maximal predictive ability by Harrell\'s C-statistics. The best-performing PRS for each derivation GWAS was evaluated in another independent case-cohort dataset (260 breast cancer cases and 7845 sub-cohorts of Japanese females during a median follow-up of 16.9 years).
RESULTS: For the best PRS model involving 46,861 single nucleotide polymorphisms (SNPs; P + T method with PT = 0.05 and R2 = 0.2) derived from Japanese-ancestry GWAS, the Harrell\'s C-statistic was 0.598 ± 0.018 in the evaluation dataset. The age-adjusted hazard ratio for breast cancer in females with the highest PRS quintile compared with those in the lowest PRS quintile was 2.47 (95% confidence intervals, 1.64-3.70). The PRS constructed using Japanese-ancestry GWAS demonstrated better predictive performance for breast cancer in Japanese females than that using European-ancestry GWAS (Harrell\'s C-statistics 0.598 versus 0.586).
CONCLUSIONS: This study developed a breast cancer PRS for Japanese females and demonstrated the usefulness of the PRS for breast cancer risk stratification.
方法:使用日本和欧洲祖先的女性乳腺癌全基因组关联研究(GWAS)的公开汇总统计,我们,分别,使用修剪和阈值(PT)和具有不同参数的LDpred方法开发了31个候选全基因组PRS。在候选的PRS模型中,根据HarrellC-statistics的最大预测能力,使用病例-队列数据集(中位随访时间为11.9年的63例乳腺癌病例和2213个日本女性亚组)选择最佳模型.在另一个独立的病例队列数据集中评估了每个衍生GWAS的最佳PRS(260例乳腺癌病例和7845例日本女性子队列,中位随访时间为16.9年)。
结果:对于涉及源自日本血统GWAS的46,861个单核苷酸多态性(SNP;PT=0.05和R2=0.2的PT方法)的最佳PRS模型,在评估数据集中,Harrell的C统计量为0.598±0.018。PRS五分位数最高的女性与PRS五分位数最低的女性相比,乳腺癌的年龄校正风险比为2.47(95%置信区间,1.64-3.70)。使用日本血统GWAS构建的PRS对日本女性乳腺癌的预测性能优于使用欧洲血统GWAS的PRS(Harrell的C-statistics0.598对0.586)。
结论:这项研究为日本女性开发了乳腺癌PRS,并证明了PRS对乳腺癌风险分层的有用性。