Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

Abstract

Thymidylate synthase (TS) is the primary target of 5-fluorouracil (5-FU).A VNTR polymorphism in the TS promoter region is associated with the efficacy of 5-FU-based chemotherapy in colorectal cancer. A common G>C SNP at the 12th nucleotide of the second repeat in the TS*3 alleles has been recently described. The combination of SNP and VNTR allows the definition of 3 TS alleles: *2, *3G and *3C. The aim of our study was to evaluate the predictive value of clinical response and survival of these new defined TS alleles. TS genotypes of 89 patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-based chemotherapy were carried out. The clinical outcome was evaluated according to the genotype (high expression genotype: *2R/*3G; *3C/*3G; *3G/*3G; and low expression genotype: *2R/*2R; *2R/*3C; *3C/*3C. A higher overall response was observed in the group of patients with a low expression genotype (p ‫؍‬ 0.035). The probability of achieving a clinical response of patients with a low expression-related genotype was 2.9 higher than that of the other group (95% CI ‫؍‬ 1.03-5.6, p ‫؍‬ 0.04). The median time to progression was 12 months and 9 months in the low and high expression groups, respectively (p ‫؍‬ 0.07, log rank test). Overall survival was significantly longer in the low expression group. In this group the median OS was not achieved at 50 months of follow-up in contrast to the 20 months observed in the high expression group (p ‫؍‬ 0.03). TS genotype was an independent predictor of progression-free and overall survival in the Cox regression models after adjustment to the other clinical variables. The selection of patients who are likely to respond to 5-FU therapy may be considerably improved if the TS genotype were to include both the VNTR and the SNP located within the promoter region of the gene. © 2004 Wiley-Liss, Inc. Key words: 5-FU resistance; TS-polymorphism; colorectal cancer; fluoropyrimidine chemotherapyA high proportion of colorectal cancer, which is a leading cause of cancer-related morbidity and mortality in the Western world, is diagnosed at advanced stages when chemotherapy is required for its management. 5-Fluorouracil (5-FU) is a folate-pathway inhibitor that has been available for 50 years, and continues to be a mainstay of treatment of advanced disease. 1 This drug is a fluoropyrimidine that, on activation to the nucleotide form, develops a stable complex with thymidylate synthase (TS), inhibiting the activity of the enzyme. 2 TS catalyzes the reductive methylation of dUMP by 5,10-methylenetetrahydrofolate to form dTNP, which is a critical reaction for cell proliferation. 3 Early in vitro studies have demonstrated more resistance to 5-FU of cell lines with high TS expression 4 or transfected with wild-type TS cDNA. 5 A number of studies have been published indicating that patients with high tumor levels of TS are unlikely to respond to infusion treatment with 5-FU, whereas patients with low levels have response rates that are higher than expected. 6 -13 The agreement between these...

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy

“…Therefore, the TS functional polymorphisms are under investigation for the possibility of optimising chemotherapy (Yong and Innocenti, 2007). Studies in patients with metastatic colorectal cancer showed that carriers of the TS 5 0 -UTR 3R (3G) and/or the TS 3 0 -UTR 6 þ alleles had adverse clinical outcomes (Pullarkat et al, 2001;Etienne et al, 2002;Park et al, 2002;Marcuello et al, 2004;Stoehlmacher et al, 2004;Martinez-Balibrea et al, 2007); however, such an association was not always detected (Lecomte et al, 2004;Jakobsen et al, 2005;Ruzzo et al, 2007a, b). Heterogeneity in clinical experimental conditions (Sorbye et al, 2007), in tumour burden (Köhne et al, 2002) and in genetic/molecular features in the presence of a multisite metastatic disease (Yokota, 2000) may explain variable results in these pharmacogenetic studies.…”

Identification of a novel single nucleotide polymorphism in the first tandem repeat sequence of the thymidylate synthase 2R allele

“…14 The 3R G > C has been shown to be present in approximately half of all Caucasian 3R alleles, and is commonly referred to as 3RC to distinguish it from the wild-type 3RG. 13 When both the VNTR and 3R G > C SNP are considered together, tumors from colorectal cancer patients with the homozygous wild-type 3RG/3RG genotype have been shown to have significantly higher TS expression compared to 2R/2R, 2R/3RC or 3RC/3RC individuals, 15,16 and patients with these low expression genotypes experience significantly higher rates of response and survival after 5-FU-based chemotherapy. 14,16 The C > G SNP in the last repeat of the 2R creates a second E-box consensus sequence and potential functional USF-binding site.…”

“…13 When both the VNTR and 3R G > C SNP are considered together, tumors from colorectal cancer patients with the homozygous wild-type 3RG/3RG genotype have been shown to have significantly higher TS expression compared to 2R/2R, 2R/3RC or 3RC/3RC individuals, 15,16 and patients with these low expression genotypes experience significantly higher rates of response and survival after 5-FU-based chemotherapy. 14,16 The C > G SNP in the last repeat of the 2R creates a second E-box consensus sequence and potential functional USF-binding site. 14 In this case, the wild-type allele has been designated 2C and the variant 2G, however, in vitro studies have shown no functional difference between the two, and thus no further genotyping studies have been performed.…”

Genomics of selected human odorant receptors

“…Some groups showed that in general changes in non-coding DNA can have a tremendous impact on phenotype including drug response [27], disease susceptibility [28][29][30], and the evolution of differences between species [31]. In terms of odorant receptors in special, the dimension of influence by mutations in non-coding regions is not proved yet, and much more experiments and analysis will be required to draw conclusions how SNPs and odorant perception are related to each other.…”