title: Double-strand break damage and associated DNA repair genes predispose smokers to gene methylation.
abstract: Gene promoter hypermethylation in sputum is a promising biomarker for predicting lung cancer. Identifying factors that predispose smokers to methylation of multiple gene promoters in the lung could affect strategies for early detection and chemoprevention. This study evaluated the hypothesis that double-strand break (DSB) repair capacity and sequence variation in genes in this pathway are associated with a high methylation index in a cohort of current and former cancer-free smokers. A 50% reduction in the mean level of DSB repair capacity was seen in lymphocytes from smokers with a high methylation index, defined as three or more of eight genes methylated in sputum, compared with smokers with no genes methylated. The classification accuracy for predicting risk for methylation was 88%. Single nucleotide polymorphisms within the MRE11A, CHEK2, XRCC3, DNA-PKc, and NBN DNA repair genes were highly associated with the methylation index. A 14.5-fold increased odds for high methylation was seen for persons with seven or more risk alleles of these genes. Promoter activity of the MRE11A gene that plays a critical role in recognition of DNA damage and activation of ataxia-telangiectasia mutated was reduced in persons with the risk allele. Collectively, ours is the first population-based study to identify DSB DNA repair capacity and specific genes within this pathway as critical determinants for gene methylation in sputum, which is, in turn, associated with elevated risk for lung cancer.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.forename: Christine A
authors.initials: CA
authors.lastname: Stidley
authors.forename: Randy
authors.initials: R
authors.lastname: Willink
authors.forename: Amanda
authors.initials: A
authors.lastname: Bernauer
authors.forename: Kieu
authors.initials: K
authors.lastname: Do
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Xin
authors.initials: X
authors.lastname: Sheng
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Frasco
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
authors.forename: Christopher
authors.initials: C
authors.lastname: Zima
authors.forename: Richard E
authors.initials: RE
authors.lastname: Crowell
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D064447:Checkpoint Kinase 2; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D000076228:MRE11 Homologue Protein; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012907:Smoking / Q000453:epidemiology / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C110901:X-ray repair cross complementing protein 3; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein