Influence of thymidylate synthase gene polymorphisms on the survival of colorectal cancer patients receiving adjuvant 5-fluorouracil

Erika Hitre, Barna Budai, Vilmos Adleff, Ferenc Czeglédi, Zsolt Horváth, Fruzsina Gyergyay, József Lövey, Tibor Kovács, Zsolt Orosz, István Láng, Miklós Kásler, Judit Kralovánszky

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

The present study aimed to prospectively investigate the influence of thymidylate synthase (TS) polymorphisms (5′-TSER, 3′-TSUTR) on the disease-free survival (DFS) and overall survival (OS) of patients with colorectal cancer (CRC) who were treated with adjuvant 5-fluorouracil (5-FU) therapy. Patients were followed up for 19 ± 14 months (median ± SD). TS genotypes were determined from the peripheral blood mononuclear cells of 166 patients by polymerase chain reaction-polyacrylamide gel electrophoresis and restriction fragment length polymorphism methods. 5′-TSER 3R homozygotes showed significantly longer DFS (P=0.048) and OS (P=0.009). The 5′-TSER and 3′-TSUTR genotype combination groups showed a significant difference for DFS (P=0.039) and OS (P=0.029). Significantly better DFS (P=0.049) and OS (P=0.043) were observed for 6 bp/6 bp genotypes in 5′-TSER heterozygotes (n=80). Based on this, and on hazard ratios obtained by Cox regression analysis of the DFS of genotype-combinations, the patients were classified as belonging to prognostic groups A and B. The DFS and OS of these two groups showed a highly significant difference (P=0.002 and 0.001). In the multivariate Cox regression model, beside tumour location, the prognostic classification (groups A and B) proved to be an independent prognostic factor. Our data suggest that those TS genotypes and their combinations (group A: 3R/3R with any 3′-TSUTR genotype and 2R/3R with 6 bp/6 bp), which have been reported earlier as having high TS expression, predict significantly longer DFS and OS. We found that a combination of germline TS polymorphisms is an independent prognostic marker in selecting CRC patients with worse prognosis, and it may be worthwhile to examine whether these patients would benefit from an alternative therapy.

Original languageEnglish
Pages (from-to)723-730
Number of pages8
JournalPharmacogenetics and Genomics
Volume15
Issue number10
DOIs
Publication statusPublished - Oct 2005

Keywords

  • Adjuvant 5-FU therapy
  • Colorectal cancer
  • Disease-free survival
  • Overall survival
  • Thymidylate synthase polymorphisms

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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