Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients

Pharmacogenetics. 2004 Dec;14(12):785-92. doi: 10.1097/00008571-200412000-00001.

Abstract

Methylenetetrahydrofolate reductase (MTHFR) controls intracellular CH2FH4 concentrations (required for optimal fluoropyrimidine efficacy) by irreversibly converting CH2FH4 into 5-methyltetrahydrofolate. MTHFR 677C>T and 1298A>C polymorphisms are linked to altered enzyme activity. Thus, mutated MTHFR tumours should, in theory, be more sensitive to 5-fluorouracil (5FU) than wild-type tumours. MTHFR polymorphisms in position 677 and 1298 were analysed in 98 colorectal cancer patients with unresectable liver metastases (57 men, 41 women, mean age 64 years) receiving 5FU-folinic acid. 677C>T and 1298A>C genotypes were determined simultaneously by melting curve analyses on liver metastases. 677C>T genotype distribution was 46.9% wt/wt, 34.7% wt/mut and 18.4% mut/mut; that of 1298A>C was 52.0% wt/wt, 35.7% wt/mut and 12.3% mut/mut. The response rate was not related to 1298A>C genotype but was significantly linked to 677C>T genotype (response rate: 40%, 21% and 56% in wt/wt, wt/mut and mut/mut, respectively; P = 0.040), with an increased response rate in mut/mut tumours relative to wt/wt (odds ratio = 1.88). Thymidylate synthase activity measured in metastases was a significant predictor of 5FU responsiveness and the addition of the 677C>T genotype improved model prediction. MTHFR 1298A>C polymorphism was significantly linked to specific survival, with homozygous mutated patients having the worst prognosis (P = 0.009, relative risk = 2.48 in mut/mut versus wt/wt). MTHFR 1298A>C genotype remained a significant predictor in a multivariate analysis including metastasis characteristics. The results suggest that MTHFR genotypes are relevant and independent factors of patient outcome in 5FU-based treatment of advanced colorectal cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / secondary
  • European Continental Ancestry Group
  • Female
  • Fluorouracil / therapeutic use*
  • France
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Middle Aged
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Staging
  • Pharmacogenetics
  • Polymorphism, Genetic*
  • Prognosis
  • Retrospective Studies
  • Risk
  • Survival Rate

Substances

  • Antimetabolites, Antineoplastic
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Fluorouracil