An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study

Yifei Cheng; Lang Wu; Junyi Xin; Shuai Ben; Silu Chen; Huiqin Li; Lingyan Zhao; Meilin Wang; Gong Cheng; Mulong Du

doi:10.1186/s12967-024-05190-y

An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study

J Transl Med. 2024 Apr 17;22(1):366. doi: 10.1186/s12967-024-05190-y.

Authors

Yifei Cheng^#^{1

2}, Lang Wu^#³, Junyi Xin^#⁴, Shuai Ben^#^{1

2

5}, Silu Chen^{1

2}, Huiqin Li⁶, Lingyan Zhao^{1

2}, Meilin Wang^{1

2

7}, Gong Cheng⁸, Mulong Du^{9

10}

Affiliations

¹ Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Department of Environmental Genomics, School of Public Health, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
² The Key Laboratory of Modern Toxicology of Ministry of Education, Department of Genetic Toxicology, School of Public Health, Center for Global Health, Nanjing Medical University, Nanjing, China.
³ Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
⁴ Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.
⁵ Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
⁶ Department of Biostatistics, School of Public Health, Center for Global Health, Nanjing Medical University, Nanjing, China.
⁷ Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China.
⁸ Department of Urology, The First Affiliated Hospital of Nanjing Medical University & Jiangsu Province People's Hospital, 300 Guangzhou Road, Nanjing, 210029, China. gcheng@njmu.edu.cn.
⁹ Department of Biostatistics, School of Public Health, Center for Global Health, Nanjing Medical University, Nanjing, China. mulongdu@hsph.harvard.edu.
¹⁰ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA. mulongdu@hsph.harvard.edu.

^# Contributed equally.

Abstract

Background: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification.

Methods: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes.

Results: The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99-2.78] than LOPC (HR = 1.95, 95% CI 1.89-2.01; I² = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98-5.54) but not to LOPC (HR = 0.98, 95% CI 0.96-1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I² = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures.

Conclusions: This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

Keywords: Age-specific genome-wide association studies; Early-onset prostate cancer; Phenome-wide association studies; Polygenic risk score; UK biobank.

MeSH terms

Cohort Studies
Genetic Predisposition to Disease
Genetic Risk Score*
Genome-Wide Association Study
Humans
Male
Prostatic Neoplasms*
Risk Factors