• 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.
• 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; Nanjing Municipal Center for Disease Control and Prevention, Nanjing, China.
• 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 Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, China.
• 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. Electronic address: drzdzhang@njmu.edu.cn.
• 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. Electronic address: mwang@njmu.edu.cn.

BACKGROUND: Fine particulate matter (PM_2.5) is suspected to increase the risk of colorectal cancer, but the mechanism remains unknown. We aimed to investigate the association between PM_2.5 exposure, genetic variants and colorectal cancer risk in the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening trial.

METHODS: We included a prospective cohort of 139,534 cancer-free individuals from 10 United States research centers with over ten years of follow-up. We used a Cox regression model to assess the association between PM_2.5 exposure and colorectal cancer incidence by calculating the hazard ratio (HR) and 95% confidence interval (CI) with adjustment for potential confounders. The polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between PM_2.5 exposure and genetic variants in regard to colorectal cancer risk.

RESULTS: After a median of 10.43 years of follow-up, 1,666 participants had been diagnosed with colorectal cancer. PM_2.5 exposure was significantly associated with an increased risk of colorectal cancer (HR = 1.27; 95% CI = 1.17-1.37 per 5 μg/m³ increase). Five independent susceptibility loci reached statistical significance at P < 1.22 × 10^-8 in the interaction analysis. Furthermore, a joint interaction was observed between PM_2.5 exposure and the PRS based on these five loci with colorectal cancer risk (P = 3.11 × 10^-29). The Gene Ontology analysis showed that the vascular endothelial growth factor (VEGF) receptor signaling pathway was involved in the biological process of colorectal cancer.

CONCLUSIONS: Our large-scale analysis has shown for the first time that long-term PM_2.5 exposure potential increases colorectal cancer risk, which might be modified by genetic variants.