Breast cancer (BC) is a complex disease affecting one in eight women in the USA. Advances in population genomics have led to the development of polygenic risk scores (PRSs) with the potential to augment current risk models, but replication is often limited. We evaluated 2 robust PRSs with 313 and 3820 SNPs and the effects of multiple genotype imputation replications in BC cases and control populations. Biological samples from BC cases and cancer-free controls were drawn from three European ancestry cohorts. Genotyping on the Illumina Global Screening Array was followed by stringent quality control measures and 20 genotype imputation replications. A total of 468 unrelated cases and 4337 controls were scored, revealing significant differences in mean PRS percentiles between cases and controls (p< 0.001) for both SNP sets (313-SNP PRS: 52.81 and 48.07; 3820-SNP PRS: 55.45 and 49.81), with receiver operating characteristic curve analysis showing area under the curve values of 0.596 and 0.603 for the 313-SNP and 3820-SNP PRS, respectively. PRS fluctuations (from ~2–3% up to 9%) emerged across imputation iterations. Our study robustly reaffirms the predictive capacity of PRSs for BC by replicating their performance in an independent BC population and showcases the need to average imputed scores for reliable outcomes.
乳腺癌是一种复杂疾病，在美国每八位女性中就有一人罹患。群体基因组学的发展推动了多基因风险评分（PRS）的建立，该评分体系有望增强现有风险模型的预测能力，但其可重复性常受限制。本研究评估了包含313个和3820个SNP的两种稳健PRS模型，并分析了在乳腺癌病例与对照人群中多次基因型插补复现对结果的影响。研究样本来源于三个欧洲血统队列的乳腺癌病例及无癌对照者生物样本。采用Illumina全球筛查芯片进行基因分型后，实施严格质控并进行20次基因型插补复现。最终对468例无亲缘关系病例及4337例对照者进行评分，结果显示两组SNP集合的PRS百分位数均值在病例组与对照组间均存在显著差异（p<0.001）（313-SNP PRS：52.81 vs 48.07；3820-SNP PRS：55.45 vs 49.81）。受试者工作特征曲线分析显示，313-SNP与3820-SNP PRS的曲线下面积分别为0.596和0.603。在不同插补迭代中观察到PRS值存在波动（波动范围约2-3%至9%）。本研究通过在独立乳腺癌人群中复现PRS的预测效能，有力证实了其对乳腺癌的预测能力，同时表明需对插补评分进行平均处理以获得可靠结果。
Breast Cancer Polygenic Risk Score Validation and Effects of Variable Imputation
肿瘤(癌症)患者之家