title: Genetic determinants for promoter hypermethylation in the lungs of smokers: a candidate gene-based study.
abstract: The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here, we identified genetic determinants for this epigenetic process and examined their biologic effects on gene regulation. A two-stage approach involving discovery and replication was used to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (N = 1,434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P < 8.2 × 10(-5)) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These single-nucleotide polymorphisms (SNP) were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, University of New Mexico, Albuquerque, New Mexico 87108, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.forename: Christine A
authors.initials: CA
authors.lastname: Stidley
authors.forename: Yushi
authors.initials: Y
authors.lastname: Liu
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.forename: Randall P
authors.initials: RP
authors.lastname: Willink
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Michael
authors.initials: M
authors.lastname: Thun
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Bruse
authors.forename: Richard E
authors.initials: RE
authors.lastname: Crowell
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D015331:Cohort Studies; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D019175:DNA Methylation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012907:Smoking; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C000607892:LIG1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011088:DNA Ligases; D000072481:DNA Ligase ATP