title: Smoking-associated DNA methylation markers predict lung cancer incidence.
abstract: Newly 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 atAHRR(cg05575921),6p21.33(cg06126421), andF2RL3(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.
  
  
  
  Pronounced 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 ofAHRR,6p21.33, andF2RL3compared 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.
  
  
  
  AHRR,6p21.33, andF2RL3methylation 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.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yan
authors.identifier: 0000-0001-9913-6490
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Research Group Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Magdeldin
authors.initials: M
authors.lastname: Elgizouli
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: Saarland Cancer Registry, Saarbrücken, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Holleczek
authors.affiliation: Center for Chronic Immunodeficiency (CCI), Research Group Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nieters
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018179:Receptors, Thrombin / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D012907:Smoking / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005819:Genetic Markers; D018179:Receptors, Thrombin; D012097:Repressor Proteins; C492162:AHRR protein, human; C112908:protease-activated receptor 4
keywords: AHRR; DNA methylation; F2RL3; Lung cancer; Risk prediction; Smoking