Bladder cancer, a common neoplasm, is primarily caused by tobacco smoking. Epigenetic alterations including DNA methylation have the potential to be used as prospective markers of increased risk, particularly in at-risk populations such as smokers. We aimed to investigate the potential of smoking-related white blood cell (WBC) methylation markers to contribute to an increase in bladder cancer risk prediction over classical questionnaire-based smoking metrics (i.e., duration, intensity, packyears) in a nested case-control study within the prospective prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial and the alpha-tocopherol, beta-carotene cancer (ATBC) Prevention Study (789 cases; 849 controls). We identified 200 differentially methylated sites associated with smoking status and 28 significantly associated (after correction for multiple testing) with bladder cancer risk among 2670 previously reported smoking-related cytosine-phosphate-guanines sites (CpGs). Similar patterns were observed across cohorts. Receiver operating characteristic (ROC) analyses indicated that cg05575921 (AHHR), the strongest smoking-related association we identified for bladder cancer risk, alone yielded similar predictive performance (AUC: 0.60) than classical smoking metrics (AUC: 0.59-0.62). Best prediction was achieved by including the first principal component (PC1) from the 200 smoking-related CpGs alongside smoking metrics (AUC: 0.63-0.65). Further, PC1 remained significantly associated with elevated bladder cancer risk after adjusting for smoking metrics. These findings suggest DNA methylation profiles reflect aspects of tobacco smoke exposure in addition to those captured by smoking duration, intensity and packyears, and/or individual susceptibility relevant to bladder cancer etiology, warranting further investigation.
European journal of epidemiology. 2024 Mar 30 [Epub ahead of print]
Roel Vermeulen, Barbara Bodinier, Sonia Dagnino, Rin Wada, Xuting Wang, Debra Silverman, Demetrius Albanes, Neal Freedman, Mohammad Rahman, Douglas Bell, Marc Chadeau-Hyam, Nathaniel Rothman
Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, PO Box 80178, 3508 TD, Utrecht, The Netherlands. ., Faculty of Medicine, School of Public Health, Department of Epidemiology and Biostatistics, Imperial College London, London, UK., Immunity Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, Durham, NC, USA., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.