title: Effect of CYP1A1 MSPI polymorphism on the relationship between TP53 mutation and CDKN2A hypermethylation in non-small cell lung cancer.
abstract: OBJECTIVE
  The molecular mechanisms of lung cancer susceptibility have not been fully understood. Although it has been described that germline polymorphisms are associated with either mutation or methylation of genes, the link between gene polymorphisms and gene-gene interactions has not been investigated. Therefore, we conducted this study to determine whether CYP1A1/GSTM1 polymorphisms can affect the relationship between TP53 mutation and CDKN2A hypermethylation in lung cancer.
  
  
  METHODS
  This study included 196 primary non-small cell lung cancer (NSCLC) patients. CYP1A1 MSPI and GSTM1 polymorphisms were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes. TP53 mutations of exons 5 through 9 and CDKN2A promoter hypermethylation in both cancer tissues and corresponding normal tissues were analyzed by direct sequencing and methylation-specific PCR (MSP) respectively.
  
  
  RESULTS
  TP53 mutation in the tumor was associated with squamous cell histology and CDKN2A methylation was associated with older age (≥60 years), heavy smoking (>30 pack-years), squamous cell histology and advanced stage (stage II-IV). After adjusting for age, sex, smoking degree, histology type and TNM stage, the correlation between TP53 mutation and CDKN2A methylation was significant in patients with CYP1A1 risk genotype (p = 0.038), but not in those with CYP1A1 homogeneity wild genotype (p = 0.151).
  
  
  CONCLUSIONS
  This may suggest that TP53 mutation and CDKN2A methylation specifically interact to promote lung tumorigenesis in subjects with CYP1A1 risk genotype but not in those with CYP1A1 wild-type homozygotes, implying different pathways for the development of lung carcinoma with respect to CYP1A1 polymorphism.
authors.affiliation: Environmental Epigenetics Laboratory, Department of Environmental Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Tan
authors.forename: He-Yun
authors.initials: HY
authors.lastname: Xu
authors.forename: Chen-Ye
authors.initials: CY
authors.lastname: Zhang
authors.forename: Hu
authors.initials: H
authors.lastname: Zhang
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Zhang
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Jin
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1