Methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C haplotypes: New prognostic factors in chronic lymphocytic leukemia

Abstract

6524 Background: Methylenetetrahydrofolate reductase (MTHFR) regulates the metabolism of folate and methionine, important components of DNA synthesis and methylation. Two common genetic polymorphisms (677C>T and 1298A>C) are associated with reduced MTHFR activity. We investigated whether MTHFR genotypes are associated with an increased risk for chronic lymphocytic leukaemia (CLL) or might predict disease progression in CLL patients. Methods: We genotyped the two MTHFR polymorphisms using DNA from 111 patients with CLL and 92 healthy controls using PCR amplification followed by restriction analysis. Results: Comparing the CLL patients with the healthy controls we found no significant differences in allele frequencies or genotype distributions for both polymorphisms. Progression-free-survival (PFS), a surrogate marker for disease progression, was not significant different in individuals with CLL, if all disease stages were included. However, in patients with stage A according to Binet PFS was significantly longer in patients displaying the MTHFR 677CC (p= 0.0423) and the MTHFR 1298A/C or CC genotypes (p= 0,0189), respectively. In a multivariate analysis a MTHFR haplotype (677 CC plus 1298 CC or A/C) was the best independent prognostic factor for PFS comparing with other known prognostic factors. In a subgroup analysis of prognostically more favourable, ZAP-70 negative CLL patients the two MTHFR polymorphisms, and especially the MTHFR haplotype, could separate patients into two groups with different PFS. Conclusions: Our data suggest that the MTHFR 677C>T and MTHFR 1298A>C polymorphisms do not affect the risk for B-CLL. However, MTHFR genotypes may be independent prognostic markers, which influence the PFS in patients with B-CLL. No significant financial relationships to disclose.