title: Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients.
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.
authors.affiliation: Centre Antoine Lacassagne, Nice, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Formento
authors.forename: Maurice
authors.initials: M
authors.lastname: Chazal
authors.forename: Mireille
authors.initials: M
authors.lastname: Francoual
authors.forename: Nicolas
authors.initials: N
authors.lastname: Magné
authors.forename: Patricia
authors.initials: P
authors.lastname: Formento
authors.forename: André
authors.initials: A
authors.lastname: Bourgeon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Delpero
authors.forename: Christian
authors.initials: C
authors.lastname: Letoublon
authors.forename: Denis
authors.initials: D
authors.lastname: Pezet
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005602:France; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D012306:Risk; D015996:Survival Rate; D044465:White People
chemical_list: D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil