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

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.

Association between polymorphisms in the thymidylate synthase gene and risk of breast cancer in a Mexican population

“…The TS gene is located in chromosome 18p11.32, and a tandem repeat polymorphism has been identified in the 5'-untranslated region (UTR) enhancer region of the TS promoter (TSER, rs34743033). TSER is located immediately upstream of the ATG codon initiation start site, which contains triple (TSER 3R) or double (TSER 2R) repeats of 28-bp sequences (Hitre et al, 2005). In vitro and in vivo studies have shown that TS expression is TSER-genotype dependent, and that the 3R allele is associated with a higher TS expression level (Kawakami et al, 1999).…”

Clinical implications of genetic polymorphisms on stomach cancer drug therapy

“…In colorectal cancer (CRC) patients, the combination of 5 0 UTR and 3 0 UTR TYMS polymorphisms could discriminate between high and low responders in terms of improved DFS, with better survival in individuals carrying the low-expressing alleles. 5,6 However, an opposite trend has been reported by Jakobsen et al 7 Differences reported among studies could be due to several factors including genotyped tissues (healthy or tumor), which employed a different method of drug administration and a different treatment setting (metastatic disease vs adjuvant therapy). In any case, it is likely that a single polymorphism of TYMS is not sufficient to explain changes in the clinical benefit of 5-FU, and complex combinations of variants should be considered.…”

Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer

“…However, the results are conflicting and there is no consensus on the clinical value of these variants [9][10][11]. For instance, while some studies report association between a favorable clinical response and variants at the 5′UTR and 3′UTR regulatory regions of the TYMS gene, other reports have failed to replicate such results [12][13][14][15][16]. None of these studies was performed on the Latin-American populations and studies in this group may contribute to the understanding of the biological significance of TYMS variants and their pharmacological relevance for CRC patients undergoing chemotherapy.…”