The MTHFD1 1958G>A Relates to Survival Rate According to PBMCs DNA Global Methylation in Cancer

Abstract

Several polymorphic gene variants within one-carbon metabolism are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon gene variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism variants in hepatocellular-carcinoma (HCC), cholangiocarcinoma (CC) and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping of 10 one-carbon genes polymorphisms was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p=0.007) and related to 63% reduction of the overall cancer risk (OR=0.37, p=0.003) and 75% of risk for colon cancer (OR=0.25, p=0.006). The MTHFD1 1958GG was significantly more frequent among cancer patients (p=0.007) and associated to lower DNA methylation as compared to 1958GA and 1958AA (p=0.048). No differences were found in terms of cancer risk and DNA methylation according to the other polymorphisms analysed. The MTHFD1 1958GG genotype is more frequent in cancer patients and associated to PBMCs DNA hypomethylation as compared to the MTHFD1 1958AA genotype that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.