Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy.
OBJECTIVE
Fluorouracil (5-FU) is widely used in the treatment of colorectal cancer. Methylenetetrahydrofolate reductase (MTHFR) could play an important role in the action of 5-FU, an inhibitor of thymidylate synthetase, by converting 5,10-methylenetetrahydrofolate, a substrate of thymidylate synthetase, to 5-methyltetrahydrofolate. A polymorphism in MTHFR (677 C-->T; A222V) reduces enzyme activity and presumably increases the level of 5,10-methylenetetrahydrofolate. This increase would be expected to correlate with an improved response to 5-FU. The aim of the present study was to investigate the association between the MTHFR polymorphism and response to 5-FU and other fluoropyrimidines in patients with metastatic colorectal cancer.


METHODS
Forty-three patients with metastatic colorectal adenocarcinoma were analyzed. All patients were treated with p.o. or i.v. fluoropyrimidine-based chemotherapy. A comprehensive chart examination was performed to determine tumor response rates. Genomic DNA was extracted from blood, and MTHFR genotypes were determined.


RESULTS
At least one copy of the mutant valine allele was present in 26 patients (21 heterozygotes and 5 homozygotes). The remaining 17 patients carried only the alanine allele. Exploration of the relationship between MTHFR alleles and response rates revealed a statistically significant difference in the frequency of the valine allele among responders versus nonresponders (P = 0.0351). This observation was associated with an odds ratio of 2.86 (95% confidence interval 1.06-7.73) for a response in individuals with a valine allele.


CONCLUSIONS
Our results show a link between the MTHFR polymorphism and tumor response to fluoropyrimidine-based chemotherapy and suggest that MTHFR genotyping may be of predictive benefit in selecting treatment regimens.
Department of Medicine, McGill University, Montreal, Canada.
Victor
V
Cohen
Valerie
V
Panet-Raymond
Nelly
N
Sabbaghian
Isabelle
I
Morin
Gerald
G
Batist
Rima
R
Rozen
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D000069287:Capecitabine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil