| Title: | An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study |
| Journal: | Journal of Translational Medicine |
| Published: | 17 Apr 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38632662/ |
| DOI: | https://doi.org/10.1186/s12967-024-05190-y |
| URL: | https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-05190-y |
Publication 9879
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Abstract
BackgroundEarly-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.MethodsWe 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.ResultsThe 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 cancerAge-basedPheWAS; https://mulongdu.shinyapps.io/proap), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures.ConclusionsThis 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.</p>
10 Authors
- Yifei Cheng
- Lang Wu
- Junyi Xin
- Shuai Ben
- Silu Chen
- Huiqin Li
- Lingyan Zhao
- Meilin Wang
- Gong Cheng
- Mulong Du
1 Application
| Application ID | Title |
|---|---|
| 45611 | Genome-wide cross-trait analysis for genetic architecture of pan-cancer by UK Biobank |
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