The RFC1 80G>A Relates to Survival Rate According to PBMCs DNA Global Methylation in Primary Liver Cancer

Abstract

One-carbon metabolism regulates both nucleotide synthesis and biological methylation including that of DNA. DNA methylation is altered in cancer disease and variants of one-carbon metabolism genes have been associated to cancer risk. Aim of this study was to investigate a possible link among polymorphic variants, global DNA methylation in peripheral blood mononuclear cells (PBMCs) and cancer survival rate in human primary liver cancer. Forty-seven patients (31 hepatocellular carcinoma and 16 cholangiocarcinoma) were genotyped for 10 one-carbon genes polymorphisms. The methylcytosine (mCyt) content was measured by LC/MS/MS in PBMCs DNA. The homozygous AA variant of RFC1 80G>A was associated with a significantly reduced survival rate as compared to GG and GA (p=0.005). Moreover, when the mCyt levels were stratified as high (>5.34%) or low (蠄5.34%) according to the mCyt mean value, the combination of AA genotype with low mCyt led to a significantly worse survival as compared to G carriership (p<0.0001); no difference was found between G carriers and AA when associates to high mCyt (p=0.919). Moreover, a higher mortality risk was associated with the concomitant presence ofAA genotype and low mCyt, as compared to G carrier subjects (OR=8.35, p=0.001). In conclusion, in primary liver cancers RFC1 80G>A influences the survival rate, and the AA genotype combined with low PBMCs mCyt content is associated with poorer prognosis and higher mortality risk.