Abstract Objectives: A polygenic hazard score (PHS1)--weighted sum of 54 single-nucleotide polymorphism genotypes--was previously associated with age at prostate cancer (PCa) diagnosis and improved PCa screening accuracy in Europeans. Performance in more diverse populations is unknown. We evaluated PHS association with PCa in multi-ethnic populations. Design: PHS1 was adapted for compatibility with genotype data from the OncoArray project (PHS2) and tested for association with age at PCa diagnosis, at aggressive PCa diagnosis, and at PCa death. Setting: Multiple international institutions. Participants: Men with available OncoArray data from the PRACTICAL consortium who were not included in PHS1 development/validation. Main Outcomes and Measures: PHS2 was tested via Cox proportional hazards models for age at PCa diagnosis, age at aggressive PCa diagnosis (any of: Gleason score ≥7, stage T3-T4, PSA≥10 ng/mL, nodal/distant metastasis), and age at PCa-specific death. Results: 80,491 men of various self-reported race/ethnicities were included (30,575 controls, 49,916 PCa cases; genetic ancestry groups: 71,856 European, 6,253 African, 2,382 Asian). Median age at last follow-up was 70 years (IQR 63-76); 3,983 PCa deaths, 5,806 other deaths, 70,702 still alive. PHS2 had 46 polymorphisms: 24 directly genotyped and 22 acceptable proxies (r2≥0.94). PHS2 was associated with age at PCa diagnosis in the multi-ethnic dataset (z=54, p<10-16) and in each genetic ancestry group: European (z=56, p<10-16), Asian (z=47, p<10-16), African (z=29, p<10-16). PHS2 was also associated with age at aggressive PCa diagnosis in each genetic ancestry group (p<10-16) and with age of PCa death in the full dataset (p<10-16). Comparing the 80th and 20th percentiles of genetic risk, men with high PHS had hazard ratios of 5.3 [95% CI: 5.0-5.7], 5.9 [5.5-6.3], and 5.7 [4.6-7.0] for PCa, aggressive PCa, and PCa-specific death, respectively. Within European, Asian, and African ancestries, analogous hazard ratios for PCa were 5.5 [5.2-5.9], 4.5 [3.2-6.3], and 2.5 [2.1-3.1], respectively. Conclusions: PHS2 is strongly associated with age at PCa diagnosis in a multi-ethnic dataset. PHS2 stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal PCa.

中文翻译：

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多基因危险评分与多族裔人群的前列腺癌相关

摘要目的：多基因危险评分（PHS1）是54种单核苷酸多态性基因型的加权总和，以前与前列腺癌（PCa）诊断时的年龄有关，并提高了欧洲人的PCa筛查准确性。在更多样化的人群中的表现尚不清楚。我们评估了多民族人群中PHS与PCa的关联。设计：将PHS1修改为与OncoArray项目（PHS2）的基因型数据兼容，并在PCa诊断，积极的PCa诊断和PCa死亡时测试其与年龄的关联。地点：多个国际机构。参与者：具有来自PRACTICAL财团的可用OncoArray数据的人，这些人未包括在PHS1开发/验证中。主要结果和措施：通过Cox比例风险模型对PHS2进行了PCa诊断时的年龄测试，积极PCa诊断的年龄（格里森评分≥7，T3-T4期，PSA≥10 ng / mL，淋巴结转移/远处转移）和PCa特异性死亡的年龄。结果：包括80491名具有各种自我报告的种族/民族的男性（30 575名对照，49 916名PCa病例；遗传血统组：71,856名欧洲人，6,253名非洲人，2,382名亚洲人）。上次随访的中位年龄为70岁（IQR 63-76）；PCa死亡3,983，其他死亡5,806，尚活着70,702。PHS2具有46个多态性：24个直接基因分型和22个可接受的代理（r2≥0.94）。在多种族数据集（z = 54，p <10-16）和每个遗传祖先组中，PHS2与PCa诊断时的年龄相关：欧洲（z = 56，p <10-16），亚洲（z = 47） ，p <10-16），非洲（z = 29，p <10-16）。在每个遗传谱系中，在积极进行PCa诊断时，PHS2也与年龄相关（p < 10-16）以及完整数据集中PCa死亡的年龄（p <10-16）。比较80％和20％的遗传风险，高PHS的男性对PCa，侵袭性PCa的危险比分别为5.3 [95％CI：5.0-5.7]，5.9 [5.5-6.3]和5.7 [4.6-7.0]。特定于PCa的死亡。在欧洲，亚洲和非洲的祖先中，PCa的相似危害比分别为5.5 [5.2-5.9]，4.5 [3.2-6.3]和2.5 [2.1-3.1]。结论：在多种族数据集中，PHS2与PCa诊断时的年龄密切相关。PHS2通过任何，侵略性和致命PCa的遗传风险将欧洲，亚洲和非洲血统的男人分类。和特定于PCa的死亡。在欧洲，亚洲和非洲的祖先中，PCa的相似危害比分别为5.5 [5.2-5.9]，4.5 [3.2-6.3]和2.5 [2.1-3.1]。结论：在多种族数据集中，PHS2与PCa诊断时的年龄密切相关。PHS2通过任何，侵略性和致命PCa的遗传风险将欧洲，亚洲和非洲血统的男人分类。和特定于PCa的死亡。在欧洲，亚洲和非洲的祖先中，PCa的相似危害比分别为5.5 [5.2-5.9]，4.5 [3.2-6.3]和2.5 [2.1-3.1]。结论：在多种族数据集中，PHS2与PCa诊断时的年龄密切相关。PHS2通过任何，侵略性和致命PCa的遗传风险将欧洲，亚洲和非洲血统的男人分类。