Heterozygote deficiency in thymidylate synthase enhancer region polymorphism genotype distribution in Hungarian colorectal cancer patients

Abstract

Thymidylate synthase (TS) gene polymorphisms are important as prognostic factors in cancer chemotherapy, but recent results describe that the TS enhancer region (TSER) polymorphic genotypes may also modulate risk for malignancies. Two functionally important and ethnically diverse polymorphisms are present on the TS transcript, TSER, a repeat polymorphism (2 or 3 repeats; 2R, 3R) affecting TS expression, and a 6 bp ins/del polymorphism on the 3 UTR (position TS1494, del6 or ins6), which may influence mRNA stability. Hungarian population has one of the highest colorectal cancer (CRC) mortality rates in Europe, and several elevated dietary risk factors affect a large part of the population. In our study (99 primary CRC cases), population analysis of the patient group genotype frequencies revealed a departure from the Hardy-Weinberg equilibrium and significant heterozygote deficiency (p < 0.05) at the TSER locus. Despite the strong linkage between the 2 polymorphic loci, case TS1494del genotype frequencies were normally distributed, as well as the genotype frequencies of the healthy control population (n ‫؍‬ 102), at both loci. Case-control comparison demonstrated a lower relative risk of TSER heterozygotes (OR ‫؍‬ 0.47; CI ‫؍‬ 0.27-0.83; p ‫؍‬ 0.008) and a possible higher prevalence of the 3R3R&ins6/del6 in the CRC group. The observation that heterozygotes are those less susceptible for CRC in the Hungarian population may support the possibility of 2 different pathways in which TS may play a role in colorectal carcinogenesis, probably nutrient (or folate)-dependently. The lack of similar genotype effect seen with TS1494del polymorphism and the increased presence of one genotype combination (3R3R&ins6/del6) in the patient group suggest a possible TS haplotype effect influencing CRC risk.

Polymorphisms of Thymidylate Synthase in the 5′- and 3′-Untranslated Regions and Gastric Cancer

“…A study conducted by Krajinovic et al showed that genotyping of TS might make it possible to individualize treatment for patients with acute lymphoblastic leukaemia [35]. A case-control study conducted by Adleff et al showed that increased presence of one genotype combination (3R/3R and ins6/del6) in the patient group suggested a possible TS haplotype effect influencing colorectal cancer risk [36]. This supports the results achieved by us.…”

Thymidylate Synthase 5′- and 3′-Untranslated Region Polymorphisms Associated with Risk and Progression of Squamous Cell Carcinoma of the Head and Neck

“…This decreased risk was more pronounced among older never smokers, which is not consistent with data on other cancers published previously (15,18,21). Our data suggest that the TS3ЈUTR polymorphism plays an important role in the etiology of SCCHN.…”

3R Variant of Thymidylate Synthase 5'-untranslated Enhanced Region Contributes to Colorectal Cancer Risk: A Meta-analysis

“…After reviewing each original paper and extracting data, eight studies were excluded including two studies for overlapping data and six studies for studies on colorectal adenoma (Ulrich et al, 2002;Chen et al, 2004;Goode et al, 2004;Hubner et al, 2006;Hubner et al, 2007;van den Donk et al, 2007). Finally, seven case-control studies with a total of 2723 cases and 4030 controls were included into this meta-analysis (Chen et al, 2003;Adleff et al, 2004;Matsuo et al, 2005;Ulrich et al, 2005;Chen et al, 2006;Carmona et al, 2008;Karpinski et al, 2010). The detailed characteristics of these studies are summarized in Table 1.…”