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Annals of Oncology Advance Access published online on May 22, 2009
Annals of Oncology, doi:10.1093/annonc/mdp046
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer

S. Afzal1,*, S. A. Jensen2, B. Vainer3, U. Vogel4, J. P. Matsen1, J. B. Sørensen2, P. K. Andersen5 and H. E. Poulsen1

1 Department of Clinical Pharmacology, Rigshospitalet, University Hospital Copenhagen, Copenhagen N
2 Department of Oncology, Rigshospitalet, Copenhagen Ø
3 Department of Pathological Anatomy and Cytology, Rigshospitalet, Copenhagen Ø
4 Department for Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Søborg, Denmark and Institute for Science, Systems and Models, University of Roskilde, Roskilde
5 Department of Biostatistics, University of Copenhagen, København K, Denmark

* Correspondence to: Dr S. Afzal, Department of Clinical Pharmacology, Rigshospitalet, University Hospital Copenhagen, 20 Tagensvej, DK-2200, Copenhagen N, Denmark. Tel: +45-3545-7525; Fax: +45-3545-2745; E-mail: shoaib.afzal{at}rh.regionh.dk

Background: Methylenetetrahydrofolate reductase is a pivotal enzyme in folate metabolism and 5-fluorouracil (5-FU) cytotoxicity. Two common single-nucleotide polymorphisms (SNPs), MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), reduce enzyme activity. Initially, these SNPs were claimed to predict clinical efficacy, but further studies have yielded contradictory results. We tested whether these two polymorphisms are determinants of clinical outcome in a large patient group with a long follow-up time.

Patients and methods: We included 331 patients who had been treated with adjuvant 5-FU/leucovorin chemotherapy after intended curative resection between 1997 and 2003. Clinical data, including relapse rates, overall survival, and tumor stage, were collected. DNA was extracted from formalin-fixed tumor tissue and analyzed for the MTHFR 677C>T and 1298A>C SNPs with real-time PCR.

Results: The MTHFR 677C>T and 1298A>C polymorphisms were not associated with survival or relapse-free survival (P > 0.2). The 677 CC genotype was associated to toxicity (odds ratio = 1.83, P = 0.01).

Conclusions: The MTHFR 677C>T and 1298A>C polymorphisms probably do not predict efficacy of adjuvant 5-FU treatment in colorectal cancer after complete resection; however, the 677C>T polymorphism may be associated with lower toxicity in 5-FU treatment. Implementation of SNP analysis for these polymorphisms for individualized treatment is premature.

colorectal cancer, 5-fluorouracil, methylenetetrahydrofolate reductase, pharmacogenetics, single-nucleotide polymorphisms

Received for publication October 15, 2008. Revision received January 30, 2009. Accepted for publication February 3, 2009.


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