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Clinical Cancer Research Vol. 9, 1611-1615, May 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Methylenetetrahydrofolate Reductase Polymorphism in Advanced Colorectal Cancer

A Novel Genomic Predictor of Clinical Response to Fluoropyrimidine-based Chemotherapy1

Victor Cohen, Valerie Panet-Raymond, Nelly Sabbaghian, Isabelle Morin, Gerald Batist and Rima Rozen2

Departments of Medicine [V. C., G. B.], Oncology [V. C., G. B.], Pediatrics [V. P-R., N. S., I. M., R. R.], and Human Genetics [R. R.], McGill University; Centre for Experimental Therapeutics in Cancer, Jewish General Hospital [V. C., G. B.]; and Montreal Children’s Hospital Research Institute [V. P-R., N. S., I. M., R. R.], Montreal, Canada

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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Copyright © 2003 by the American Association for Cancer Research.