Smoking-associated DNA methylation markers predict lung cancer incidence

Abstract

BackgroundNewly established blood DNA methylation markers that are strongly associated with smoking might open new avenues for lung cancer (LC) screening. We aimed to assess the performance of the top hits from previous epigenome-wide association studies in prediction of LC incidence.In a prospective nested case-control study, DNA methylation at AHRR (cg05575921), 6p21.33 (cg06126421), and F2RL3 (cg03636183) were measured by pyrosequencing in baseline whole blood samples of 143 incident LC cases identified during 11 years of follow-up and 457 age- and sex-matched controls without diagnosis of LC until the end of follow-up. The individual and joint associations of the 3 markers with LC risk were estimated by logistic regression, adjusted for potential confounders including smoking status and cigarette pack-years. The predictive performance was evaluated for both the individual markers and their combinations derived from multiple algorithms.ResultsPronounced demethylation of all 3 markers was observed at baseline among cases compared to controls. Risk of developing LC increased with decreasing DNA methylation levels, with adjusted ORs (95% CI) of 15.86 (4.18–60.17), 8.12 (2.69–4.48), and 10.55 (3.44–32.31), respectively, for participants in the lowest quartile of AHRR, 6p21.33, and F2RL3 compared to participants in the highest 2 quartiles of each site among controls. The individual 3 markers exhibited similar accuracy in predicting LC incidence, with AUCs ranging from 0.79 to 0.81. Combination of the 3 markers did not improve the predictive performance (AUC = 0.80). The individual markers or their combination outperformed self-reported smoking exposure particularly in light smokers. No variation in risk prediction was identified with respect to age, follow-up time, and histological subtypes.Conclusions AHRR, 6p21.33, and F2RL3 methylation in blood DNA are predictive for LC development, which might be useful for identification of risk groups for further specific screening, such as CT examination.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0292-4) contains supplementary material, which is available to authorized users.

An epigenetic predictor of death captures multi-modal measures of brain health

“…The use of methylation-based proxies for smoking pack years and proteomic data is advantageous as methylation-based predictors are often more accurate than self-reported phenotypes, and the cost of complex proteomic platforms is negated [64]. One strength of this study is that rich data were available across the eighth decade of life, a period in which risk of cognitive decline and compromised brain integrity increases significantly.…”

Epigenetic prediction of complex traits and death

“…There were four main aims for the prediction analysis: (1) Linear regression models were used to explore aims (1) and (2). Ordinal logistic regression was used for the categorical smoking variable (never, ex, current smoker).…”

“…DNA-based predictors of health and lifestyle have potential uses in both clinical and nonclinical contexts. For example, biological predictors of smoking status and alcohol consumption may provide more accurate measurements than self-report, thereby improving disease prediction and risk stratification [1]. Here, using whole blood-derived samples, we develop novel DNA methylation-based predictors of alcohol consumption, smoking status, body mass index (BMI), and educational attainment and relate them to both a health outcome (mortality) and lifestyle characteristics in an independent cohort.…”

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

“…These epigenetic modifications are associated with an elevated risk to develop malignancies of the respiratory tract (104, 108, 109) and thus imply a putative role of AhRR in lung carcinogenesis. As previously discussed (106), tobacco smoke is rich in PAHs and may cause an AhR-mediated induction of AhRR gene expression, which requires chromatin relaxation associated with DNA demethylation (111).…”