Hypomethylation of the XRE -1383 site is associated with the upregulation of CYP1A1 in gastric adenocarcinoma.

Owing to its broad substrate specificity of mainly xenobiotic and its preferential extrahepatic expression, cytochrome P450 1A1 (CYP1A1) is a principle member of the CYP450 detoxifying enzyme superfamily involving in carcinogenesis. In this study, we analyzed methylation status of 93 CpG sites, densely scattered within approximately 1.5 kb 5' regulatory region of CYP1A1, and its association with gene transcription in tissue cohorts dissected from 40 patients with gastric cancer. Bisulfite sequencing and the resulting methylation percentages revealed dynamically methylated CpG sites located within or around xenobiotic response elements (XRE) 4-10, and a region of consistent hypermethylation located near proximal promoter, encompassing XRE2-3. Statistical analysis revealed significant differences of the methylation percentages at CpG sites -1415 (0.032) and -1524 (P=0.041) (located at the close upstream region of XRE10) between cancerous and normal gastric tissues as well as between those with and without lymphatic involvement. Quantitative real time PCR analysis showed that the CYP1A1 gene expression significantly increased in cancerous tissues compared to their normal tissue cohort, and is significantly associated with hypomethylation at the CpG sites -1383 (P=0.018) existing within the XRE10 motif. These data suggest that the variably methylated CpG site existing in the 5' regulatory region of CYP1A1 gene, corresponding with the XRE10 regulatory region, is associated with the CYP1A1 gene upregulation and likely involved in gastric cancer incidence and metastasis. Methylation analysis of the CpG sites located within or around the XRE10 motif of the CYP1A1 promoter can be used as a potential marker to evaluate individual susceptibility to gastric cancer.