Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Genet Med. 2023 Sep;25(9):100846. doi: 10.1016/j.gim.2023.100846. Epub 2023 Apr 12.
Polygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study. The Breast Cancer in Northern Israel Study provided a separate AJ population-based case-control validation series.
All women underwent Illumina OncoArray single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]) analysis. Two PRSs were assessed, SNV142 and SNV78. A total of 221 of 2243 WE women (discovery: cases = 111; controls = 110; validation: cases = 651; controls = 1772) and 221 AJ women (cases = 121; controls = 110) were included from the UK study; the Israeli series consisted of 2045 AJ women (cases = 1331; controls = 714). EAFs were obtained from the Genome Aggregation Database.
In the UK study, the mean SNV142 PRS demonstrated good calibration and discrimination in WE population, with mean PRS of 1.33 (95% CI 1.18-1.48) in cases and 1.01 (95% CI 0.89-1.13) in controls. In AJ women from Manchester, the mean PRS of 1.54 (1.38-1.70) in cases and 1.20 (1.08-1.32) in controls demonstrated good discrimination but overestimation of BC relative risk. After adjusting for EAFs for the AJ population, mean risk was corrected (mean SNV142 PRS cases = 1.30 [95% CI 1.16-1.44] and controls = 1.02 [95% CI 0.92-1.12]). This was recapitulated in the larger Israeli data set with good discrimination (area under the curve = 0.632 [95% CI 0.607-0.657] for SNV142).
AJ women should not be given BC relative risk predictions based on PRSs calibrated to EAFs from the WE population. PRSs need to be recalibrated using AJ-derived EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.
多基因风险评分（PRS）是准确预测乳腺癌（BC）风险的重要组成部分，但需要针对特定种族进行校准。尽管某些商业上可用的 PRS 中阿什肯纳兹犹太人（AJ）群体被假定为白种欧洲人（WE）起源，但它们的效应等位基因频率（EAF）却不同。我们对来自预测筛查研究中的 WE 和 AJ 女性进行了病例对照研究。在以色列北部的乳腺癌研究中，提供了一个单独的 AJ 人群基于病例对照的验证系列。
所有女性均接受了 Illumina OncoArray 单核苷酸变异（SNV；以前的单核苷酸多态性[SNP]）分析。评估了两种 PRS，即 SNV142 和 SNV78。从英国研究中纳入了 2243 名 WE 女性中的 221 名（发现：病例= 111；对照= 110；验证：病例= 651；对照= 1772）和 221 名 AJ 女性（病例= 121；对照= 110）；以色列系列由 2045 名 AJ 女性组成（病例= 1331；对照= 714）。EAF 从基因组聚集数据库中获得。
在英国研究中，SNV142 PRS 的平均评分在 WE 人群中表现出良好的校准和区分度，病例的平均 PRS 为 1.33（95%置信区间 1.18-1.48），对照的平均 PRS 为 1.01（95%置信区间 0.89-1.13）。在来自曼彻斯特的 AJ 女性中，病例的平均 PRS 为 1.54（1.38-1.70），对照的平均 PRS 为 1.20（1.08-1.32），表明具有良好的区分度，但 BC 相对风险过高。在调整了 AJ 人群的 EAF 后，平均风险得到了纠正（病例的平均 SNV142 PRS 为 1.30（95%置信区间 1.16-1.44），对照为 1.02（95%置信区间 0.92-1.12））。这在更大的以色列数据集得到了证实，具有良好的区分度（SNV142 的曲线下面积为 0.632（95%置信区间 0.607-0.657））。
不应该根据针对 WE 人群 EAF 校准的 PRS 向 AJ 女性提供 BC 相对风险预测。PRS 需要使用 AJ 衍生的 EAF 进行重新校准。使用平均 PRS 调整比率进行简单的重新校准可能效果很好。
