MTHFR (C677T) polymorphisms and stage III colon cancer: response to therapy

Leucovorin and 5-fluorouracil (5-FU) chemotherapeutics are often used as coinhibitors of the thymidylate synthase pathway to thwart the growth of cancer cells in certain types of neoplasms. The metabolism of leucovorin is mediated through the enzyme methylenetetrahydrofolate reductase (MTHFR). A common polymorphism in the MTHFR gene has been reported to be responsible for as much as a 70% reduction in activity of this enzyme when present in the homozygous form.

A total of 51 stage III colon cancer patients were identified through our tumor registry. Non-neoplastic, archived tissue was obtained for each patient and subjected to MTHFR C677T PCR-RFLP genotyping. The MTHFR C677T allele was present in 32 patients (28 heterozygotes and 4 homozygotes). The remaining 19 patients carried only the wild-type allele. Overall survival was 42.10% (8/19) for wild types and 43.757% (14/32) for those with at least one C677T allele. Of the four homozygotes identified, three have succumbed to their cancer and one is alive with cancer.

We were unable to demonstrate a survival difference between those stage III colon cancer patients receiving leucovorin therapy that carried the MTHFR C677T allele and those that were wild type for this allele. The results of this study suggest that certain subgroups (ie, homozygotes) of patients may benefit from genotypic analysis of the MTHFR gene.