Associations of the thymidylate synthase 3¡¦UTR polymorphisms with one carbon status, lymphocytic p53 oxidative lesions and hepatocellular carcinoma progression

The aims of the study were to investigate relationships between thymidylate synthase ( TS ) 3'UTR polymorphisms. Genotypes in a 6‐bp deletion/insertion in the 3’‐untranslated region ( TS 3'UTR), blood folate and homocysteine (Hcy) levels were determined on 232 HCC patients. The frequencies of TS 3’‐UTR genotype of the study HCC patients were 52% (del6/del6), 43% in del6/ins6, and 5% in ins6/ins6. Increased frequencies of one 6‐bp insertion in the TS genotypes were associated with decreased Hcy levels (r = −0.154, P = 0.04). Compared with the (del6/del6) variant, HCC patients with at least one 6‐bp insertion variants had lower levels of AFP tumour marker (P = 0.05). Among individuals with low serum folate levels (< 14 nM), the TS del6/ins6 and ins6/ins6 variants had significantly lower levels of p53 promoter oxidative damage than the del6/del6 variant. After adjustment for multiple factors including life‐style, clinical factors and serum folate status, the odds ratios for developing large tumour (size > 3 cm) were 0.24 (95% CI: 0.07–0.08) for combined MTHR C677T mutant variants (CT+TT genotypes) and TS 3'UTR mutant variants (del6/ins6 + ins6/ins6) compared with wild type variants. This protective effect against developing large tumour was negated after further adjustment of lymphocytic p53 oxidative lesions. Taken together, our data suggested that HCC patients carrying combined genotypes with at least one mutant allele in MTHFR C677T and TS 3'UTR 6 bp‐insertion variants have reduced risks of developing large tumour, which may be mediated by amelioration of p53 oxidative lesions. Grant Funding Source : Department of Health in Taiwan