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Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China. Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, China. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Epidemiology and Biostatistics at School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China. mwang@njmu.edu.cn. Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. mwang@njmu.edu.cn. The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China. mwang@njmu.edu.cn.

Genome medicine. 2023;(1):4
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Abstract

BACKGROUND The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

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Publication Type : Meta-Analysis

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