基于人群的前瞻性队列研究：东亚常见癌症的多基因风险评分预测。

Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study.

机构信息

Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.

出版信息

Elife. 2023 Mar 27;12:e82608. doi: 10.7554/eLife.82608.

DOI:10.7554/eLife.82608

PMID:36971353

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10159619/

Abstract

BACKGROUND

To evaluate the utility of polygenic risk scores (PRSs) in identifying high-risk individuals, different publicly available PRSs for breast (n=85), prostate (n=37), colorectal (n=22), and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults.

METHODS

We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals (CI) of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.

RESULTS

A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung, and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best-performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal), 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28-34% decreased risk compared to the middle quintile. In contrast, the HR observed for quintiles 4 (female-lung: 0.95 [0.61-1.47]; male-lung: 1.14 [0.82-1.57]) and 5 (female-lung: 0.95 [0.61-1.47]) were not significantly different from that for the middle quintile.

CONCLUSIONS

Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.

FUNDING

This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (ASTAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (ASTAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health (NIH) (R01 CA144034 and UM1 CA182876).

摘要

背景

为了评估多基因风险评分（PRS）在识别高危个体中的效用，我们在一项对 21694 名中国成年人进行的前瞻性研究中，检查了用于评估乳腺癌（n=85）、前列腺癌（n=37）、结直肠癌（n=22）和肺癌（n=11）的不同公开可用的 PRS。

方法

我们使用在线 PGS 目录中编纂的权重构建了 PRS。通过分布、区分度、预测能力和校准来评估 PRS 的性能。使用 Cox 比例风险模型估计不同 PRS 水平下 20 年后常见癌症的风险比（HR）和相应的置信区间（CI）。

结果

共确定了 495 例乳腺癌、308 例前列腺癌、332 例女性结直肠癌、409 例男性结直肠癌、181 例女性肺癌和 381 例男性肺癌的发病病例。表现最佳的特定部位 PRS 的接受者操作特征曲线下面积分别为 0.61（PGS000873，乳腺癌）、0.70（PGS00662，前列腺癌）、0.65（PGS000055，女性结直肠癌）、0.60（PGS000734，男性结直肠癌）、0.56（PGS000721，女性肺癌）和 0.58（PGS000070，男性肺癌）。与中间五分位数相比，处于最高癌症特异性 PRS 五分位数的个体发生乳腺癌、前列腺癌和结直肠癌的可能性增加了 64%。对于肺癌，与中间五分位数相比，最低癌症特异性 PRS 五分位数与 28%-34%的风险降低相关。相比之下，五分位数 4（女性肺癌：0.95[0.61-1.47]；男性肺癌：1.14[0.82-1.57]）和五分位数 5（女性肺癌：0.95[0.61-1.47]）的 HR 与中间五分位数无显著差异。

结论

特定部位的 PRS 可将东亚人群患乳腺癌、前列腺癌和结直肠癌的风险分层。可能需要适当的校正因子来提高校准度。

基金

本工作得到新加坡国家研究基金会（NRF-NRFF2017-02）、新加坡精准健康研究（PRECISE）和新加坡科技研究局（ASTAR）的支持。WP Koh 得到了新加坡国立医学研究理事会（NMRC）的资助（NMRC/CSA/0055/2013）。CC Khor 得到了新加坡国家研究基金会（NRF-NRFI2018-01）的资助。Rajkumar Dorajoo 获得了新加坡科学技术研究局职业发展奖（ASTAR CDA-202D8090）和卫生部健康长寿催化剂奖（HLCA20Jan-0022）。新加坡华人健康研究由新加坡国家医学研究理事会（NMRC，新加坡）（NMRC/CIRG/1456/2016）和美国国立卫生研究院（NIH）（R01 CA144034 和 UM1 CA182876）资助。