Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer

F. Thomas, A. A. Motsinger-Reif, J. M. Hoskins, A. Dvorak, S. Roy, A. Alyasiri, R. J. Myerson, J. W. Fleshman, B. R. Tan, H. L. McLeod

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41 Scopus citations

Abstract

Background: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study.Methods: The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. Results: MTHFR 1298AC and MTHFR diplotypes (for 677CT and 1298AC) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response.Conclusion:MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.

Original languageEnglish
Pages (from-to)1654-1662
Number of pages9
JournalBritish Journal of Cancer
Volume105
Issue number11
DOIs
StatePublished - Nov 22 2011

Keywords

  • 5-FU
  • MTHFR polymorphisms
  • diarrhoea
  • mucositis
  • neoadjuvant chemoradiation
  • rectal cancer

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