Effect of CYP1A1 MSPI Polymorphism on the Relationship Between TP53 Mutation and CDKN2A Hypermethylation in Non-small Cell Lung Cancer

Background and Aims lecular 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. s tudy 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. s utation 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). sions ay 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.