An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study
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 ri...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-05190-y |
| _version_ | 1827277005337395200 |
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| author | Yifei Cheng Lang Wu Junyi Xin Shuai Ben Silu Chen Huiqin Li Lingyan Zhao Meilin Wang Gong Cheng Mulong Du |
| author_facet | Yifei Cheng Lang Wu Junyi Xin Shuai Ben Silu Chen Huiqin Li Lingyan Zhao Meilin Wang Gong Cheng Mulong Du |
| author_sort | Yifei Cheng |
| collection | DOAJ |
| description | 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; I 2 = 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 (I 2 = 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 (Pro state cancer A ge-based P heWAS; 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. |
| first_indexed | 2024-04-24T07:12:28Z |
| format | Article |
| id | doaj.art-fbbb3387f0cb4e768eba0026b4e11c62 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-24T07:12:28Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-fbbb3387f0cb4e768eba0026b4e11c622024-04-21T11:28:37ZengBMCJournal of Translational Medicine1479-58762024-04-0122111310.1186/s12967-024-05190-yAn early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort studyYifei Cheng0Lang Wu1Junyi Xin2Shuai Ben3Silu Chen4Huiqin Li5Lingyan Zhao6Meilin Wang7Gong Cheng8Mulong Du9Jiangsu 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 UniversityCancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at ManoaDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical UniversityJiangsu 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 UniversityJiangsu 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 UniversityDepartment of Biostatistics, School of Public Health, Center for Global Health, Nanjing Medical UniversityJiangsu 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 UniversityJiangsu 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 UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University & Jiangsu Province People’s HospitalDepartment of Biostatistics, School of Public Health, Center for Global Health, Nanjing Medical UniversityAbstract 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; I 2 = 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 (I 2 = 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 (Pro state cancer A ge-based P heWAS; 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.https://doi.org/10.1186/s12967-024-05190-yAge-specific genome-wide association studiesEarly-onset prostate cancerPhenome-wide association studiesPolygenic risk scoreUK biobank |
| spellingShingle | Yifei Cheng Lang Wu Junyi Xin Shuai Ben Silu Chen Huiqin Li Lingyan Zhao Meilin Wang Gong Cheng Mulong Du An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study Journal of Translational Medicine Age-specific genome-wide association studies Early-onset prostate cancer Phenome-wide association studies Polygenic risk score UK biobank |
| title | An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study |
| title_full | An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study |
| title_fullStr | An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study |
| title_full_unstemmed | An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study |
| title_short | An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study |
| title_sort | early onset specific polygenic risk score optimizes age based risk estimate and stratification of prostate cancer population based cohort study |
| topic | Age-specific genome-wide association studies Early-onset prostate cancer Phenome-wide association studies Polygenic risk score UK biobank |
| url | https://doi.org/10.1186/s12967-024-05190-y |
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