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

被引:24
作者
Xin, Junyi [1 ,2 ]
Du, Mulong [1 ,3 ]
Gu, Dongying [4 ]
Jiang, Kewei [5 ]
Wang, Mengyun [6 ,7 ]
Jin, Mingjuan [8 ,9 ]
Hu, Yeting [10 ,11 ]
Ben, Shuai [1 ,2 ]
Chen, Silu [1 ,2 ]
Shao, Wei [1 ,2 ]
Li, Shuwei [1 ,2 ]
Chu, Haiyan [1 ,2 ]
Zhu, Linjun [12 ]
Li, Chen [5 ]
Chen, Kun [8 ,9 ]
Ding, Kefeng [10 ,11 ]
Zhang, Zhengdong [1 ,2 ]
Shen, Hongbing [13 ]
Wang, Meilin [1 ,2 ,14 ]
机构
[1] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Sch Publ Hlth, Dept Environm Genom,Jiangsu Key Lab Canc Biomarker, 101 Longmian Ave,Jiangning Dist, Nanjing 211166, Peoples R China
[2] Nanjing Med Univ, Ctr Global Hlth, Sch Publ Hlth, Dept Genet Toxicol,Key Lab Modern Toxicol Minist E, Nanjing, Peoples R China
[3] Nanjing Med Univ, Ctr Global Hlth, Sch Publ Hlth, Dept Biostat, Nanjing, Peoples R China
[4] Nanjing Med Univ, Nanjing Hosp 1, Dept Oncol, Nanjing, Peoples R China
[5] Peking Univ Peoples Hosp, Dept Gastroenterol Surg, Lab Surg Oncol, Beijing Key Lab Colorectal Canc Diag & Treatment R, 11 Xizhimen South St,Xicheng Dist, Beijing, Peoples R China
[6] Fudan Univ Shanghai Canc Ctr, Canc Inst, Shanghai, Peoples R China
[7] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China
[8] Zhejiang Univ Sch Med, Biostat Sch Publ Hlth, Dept Epidemiol, Hangzhou, Peoples R China
[9] Zhejiang Univ Sch Med, Affiliated Hosp 2, Canc Inst, Hangzhou, Peoples R China
[10] Zhejiang Univ Sch Med, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent, Hangzhou, Zhejiang, Peoples R China
[11] Zhejiang Univ, Canc Ctr, Hangzhou, Zhejiang, Peoples R China
[12] First Affiliated Hosp Nanjing Med Univ, Dept Oncol, Nanjing, Peoples R China
[13] Nanjing Med Univ, Ctr Global Hlth, Sch Publ Hlth, Dept Epidemiol, Nanjing, Peoples R China
[14] Nanjing Med Univ, Affiliated Suzhou Hosp Nanjing Med Univ, Suzhou Municipal Hosp, Gusu Sch, Suzhou, Peoples R China
基金
英国医学研究理事会;
关键词
Colorectal cancer; East Asian; European; Polygenic risk score; Lifestyle; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; GENETIC RISK; HERITABILITY; METAANALYSIS;
D O I
10.1186/s13073-023-01156-9
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
BackgroundThe 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.MethodsA 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.ResultsIn the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 x 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 (P-trend = 8.15 x 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.ConclusionsIn 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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页数:14
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