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Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study |
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| Authors: | Xiaoxia Wei Dianjianyi Sun Jiaxin Gao Jing Zhang Meng Zhu Canqing Yu Zhimin Ma Yating Fu Chen Ji Pei Pei Ling Yang Iona Y. Millwood Robin G. Walters Yiping Chen Huaidong Du Guangfu Jin Zhengming Chen Zhibin Hu Liming Li Hongbing Shen Jun Lv Hongxia Ma |
| Affiliation: | 1. Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China;2. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China;3. Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China;4. Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China;5. Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK;6. Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK;7. Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK;8. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China |
| Abstract: | The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10−8. Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening. |
| Keywords: | lung cancer in never-smoking women polygenic risk score predictive markers |