Abstract
We aimed to explore the association of P16, MGMT and HMLH1 with gastric cancer and their relation with Methylenetetrahydrofolate reductase (MTHFR). 322 gastric patients who were confirmed with pathological diagnosis were included in our study. Aberrant DNA methylation of P16, MGMT and HMLH1 and polymorphisms of MTHFR C677T and A1298C were detected using PCR-RFLP. The proportions of DNA hypermethylation in P16, MGMT and hMLH1 genes in gastric cancer tissues were 75.2% (242/322), 27.6% (89/322) and 5.3% (17/322), respectively. In the remote normal-appearing tissues, 29.5% (95/322) and 16.1%(52/322) showed hypermethylation in P16 and MGMT genes, respectively. We found a significantly higher proportion of DNA hypermethylation of P16 in patients with N1 TNM stage in cancer tissues and remote normal-appearing tissues (P<0.05). Similarly, we found DNA hypermethylation of MGMT had significantly higher proportion in N1 and M1 TNM stage (P<0.05). Individuals with homozygotes (TT) of MTHFR C677T had significant risk of DNA hypermethylation of MGMT in cancer tissues [OR (95% CI)=4.27(1.76-7.84)], and a significant risk was also found in those carrying MTHFR 677CT/TT genotype [OR (95% CI)= 3.27(1.21-4.77)]. We found the aberrant hypermethylation of cancer-related genes, such as P16, MGMT and HMLH1, could be predictive biomarkers for detection of gastric cancer.
Highlights
Gastric cancer is one of the most common cancers worldwide, and it ranks the second leading cause of cancer-related deaths after lung cancer.[1]
The proportion of DNA hypermethylation in P16, MGMT and hMLH1 in cancer tissues were significantly higher than remote normal-appearing tissues
Our finding showed that individuals with homozygotes (TT) of Methylenetetrahydrofolate reductase (MTHFR) C677T had significant risk of DNA hypermethylation of MGMT in cancer tissues [Odds ratios (OR)=4.27(1.767.84)], and a significant risk was found in those carrying MTHFR 677CT/TT genotype [OR= 3.27(1.21-4.77)]
Summary
Gastric cancer is one of the most common cancers worldwide, and it ranks the second leading cause of cancer-related deaths after lung cancer.[1]. Gastric Cancer cancer.[3] The one-carbon cycle plays an important role in cellular proliferation and epigenetic modification, and folate is a important component of this pathway.[3] Folate functions as a critical source of carbon moieties in the synthesis of nucleotides, DNA repair and replication These effects of foalte may affect the susceptibility of gastric cancer.[4,5] Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism, is responsible for the circulation form of folate and 5-methyltetrahydrofolate which is involved in DNA synthesis and methylation.[6] The activity of MTHFR is controlled mainly by the genetic polymorphisms and shows variation between different individuals.[7,8] MTHFR C677T (rs1801133) and MTHFR A1298C (rs1801131) polymorphisms are associated with a reduced activity of MTHFR. We aimed to explore the association of P16, MGMT and HMLH1 with gastric cancer and their relation with MTHFR
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