Prognostic evaluation of polygenic risk score underlying pan-cancer analysis: evidence from two large-scale cohorts

Junyi Xin; Xia Jiang; Huiqin Li; Silu Chen; Zhengdong Zhang; Meilin Wang; Dongying Gu; Mulong Du; David C Christiani

doi:10.1016/j.ebiom.2023.104454

Prognostic evaluation of polygenic risk score underlying pan-cancer analysis: evidence from two large-scale cohorts

EBioMedicine. 2023 Mar:89:104454. doi: 10.1016/j.ebiom.2023.104454. Epub 2023 Feb 3.

Authors

Junyi Xin¹, Xia Jiang², Huiqin Li³, Silu Chen⁴, Zhengdong Zhang⁴, Meilin Wang⁴, Dongying Gu⁵, Mulong Du⁶, David C Christiani⁷

Affiliations

¹ Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
² Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
³ Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
⁴ Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 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.
⁵ Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: dygu@njmu.edu.cn.
⁶ Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA. Electronic address: drdumulong@njmu.edu.cn.
⁷ Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, USA.

Abstract

Background: Polygenic risk score (PRS) has been demonstrated to be effective in identifying individuals at high risk of developing cancer, but its prognostic value remains unclear.

Methods: We constructed site-specific PRSs by aggregating the risk effect of independent variants derived from previous genome-wide association studies (GWASs) across 17 cancer types. The Cox proportional hazards model was used to evaluate the association of each PRS with cancer survival, leveraging data from two prospective European cohorts, namely the UK Biobank involving 19,628 incident cases and The Cancer Genome Atlas involving 7079 prevalent cases. The combined PRS (CPRS), determined by merging site-specific PRSs, was further used to assess the prognostic effect of PRS on overall cancer in a sex-specific manner.

Findings: We discovered that the cancer risk-related PRS was associated with neither overall survival (OS) nor cancer-specific survival (CSS) of each site-specific cancer with an underlying false discovery rate (FDR) P > 0.05, as evidenced by consistent findings from the two cohorts. Furthermore, the fixed-effect meta-analysis of the two cohorts provided no evidence to support for an association between CPRS and overall cancer survival in both males [OS: hazard ratio (HR)_meta = 1.00, P_meta = 0.760; CSS: HR_meta = 1.01, P_meta = 0.447] and females (OS: HR_meta = 0.97, P_meta = 0.067; CSS: HR_meta = 0.96, P_meta = 0.054). Similar results were observed across multiple sensitivity analyses.

Interpretation: Our findings indicate that the risk-specific PRS might not be a clinically useful tool in cancer prognosis prediction and further studies focusing on the development of polygenic prognostic score are warranted.

Funding: This project was funded by the National Natural Science Foundation of China (82173601 and 82073631), and Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Keywords: Cancer; Cohort study; Epidemiology; Polygenic risk score; Survival evaluation.

Publication types

Meta-Analysis

MeSH terms

Female
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Male
Multifactorial Inheritance
Neoplasms*
Prognosis
Prospective Studies
Risk Factors

Grants and funding

R35 CA197449/CA/NCI NIH HHS/United States