title: F2RL3 methylation, lung cancer incidence and mortality.
abstract: Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age- and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were ≤0.54 compared with whose methylation intensity were ≥0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack-years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants≥65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics = 0.86 for participants≥65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Schöttker
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Network Aging Research (NAR), Heidelberg University, Heidelberg, Germany.
authors.forename: José
authors.initials: J
authors.lastname: Ordóñez-Mena
authors.affiliation: Saarland Cancer Registry, Saarbrücken, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Holleczek
authors.affiliation: Division of Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Germany.
authors.forename: Rongxi
authors.initials: R
authors.lastname: Yang
authors.affiliation: Division of Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Butterbach
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000368:Aged; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D018179:Receptors, Thrombin / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology / Q000235:genetics
chemical_list: D018179:Receptors, Thrombin; C112908:protease-activated receptor 4
keywords: F2RL3 methylation; PAR-4; lung cancer; prospective study; smoking