Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy.
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| Abstract | PURPOSE:
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. EXPERIMENTAL DESIGN: 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.
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| Authors | Victor Cohen, Valerie Panet-Raymond, Nelly Sabbaghian, Isabelle Morin, Gerald Batist, Rima Rozen |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 5 Pg. 1611-5 (May 2003) ISSN: 1078-0432 [Print] United States |
| PMID | 12738713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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