AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality

• Type of Material: Article
• Authors: Laurie Grieshober, University of Utah; Stefan Graw, University of Kansas; Matt J. Barnett, Fred Hutchinson Cancer Research Center; Mark D. Thornquist, Fred Hutchinson Cancer Research Center; Gary E. Goodman, Fred Hutchinson Cancer Research Center; Chu Chen, Fred Hutchinson Cancer Research Center; Devin C. Koestler, University of Kansas; Carmen Marsit, Emory University; Jennifer A. Doherty, University of Utah
• Language: English
• Date: 2020-09-22
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12885-020-07407-x
• Title of Journal or Parent Work: BMC CANCER
• Volume: 20
• Issue: 1
• Start Page: 905
• End Page: 905
• Grant/Funding Information: The research reported in this publication was supported by the National Center for Advancing Translational Sciences (NCATS) of the NIH under Award Number TL1 TR002540 and the National Cancer Institute (NCI) of the NIH R01 CA151989 (to J.A. Doherty), the Munck-Pfefferkorn Fund at Dartmouth College (to J.A. Doherty and C.J. Marsit), the Huntsman Cancer Foundation (to J.A. Doherty), and the Kansas IDeA Network of Biomedical Research Excellence Bioinformatics Core (to D.C. Koestler), and supported in part by the National Institute of General Medical Science (NIGMS) award P20 GM103418 (to D.E. Wright), and the NCI under award numbers P30 CA042014 (to M.E. Beckerle), P30 CA168524 (to R.A. Jensen), and R01 CA111703 (to C. Chen). Support for CARET is from NCI grants UM1 CA167462 and U01 CA63673 (to G.E. Goodman) and U01 CA167462 (to C. Chen). The funding bodies had no roles in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
• Keywords: BETA-CAROTENE; Methylation; serum biomarkers; GENES; CARET; Biomarkers; Epidemiology; PERIPHERAL-BLOOD; Life Sciences & Biomedicine; Science & Technology; Lung cancer; SIGNATURES; Mortality; EXPOSURE; Oncology; AHRR; ARYL-HYDROCARBON RECEPTOR; COMBINATION; DNA METHYLATION
• Research Categories: Health Sciences, Oncology; Health Sciences, Public Health

Abstract

Background: A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers. Methods: The β-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation β-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype. Results: Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively). Conclusions: In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.