Polymorphisms of GSTP1, ERCC2 and TS-3′UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients

Abstract

The aim of the current study was to examine whether polymorphisms in drug metabolism genes have any clinical impact on patients treated with 5-fluorouracil (FU)/oxaliplatin for metastatic colorectal cancer (MCRC). In total, 63 patients with MCRC were recruited and treated with a modified FOLFOX6 (mFOLFOX6) treatment as a first-line chemotherapy. Polymorphisms in five drug metabolism genes and two DNA-repair genes were assessed in these patients using polymerase chain reaction (PCR), a PCR restriction fragment length polymorphism (PCR-RFLP) technique or invader techniques. These included a 28-bp tandem repeat in the 5′-untranslated region (UTR) and 6-bp deletions in the 3′-UTR of thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR; Ala677Val), glutathione S-transferase π (GSTP1; IIe105Val), GST θ1 (GSTT1; deletion) and GST μ1 (GSTM1; deletion) and the two DNA-repair genes, excision repair cross-complementing-1 (ERCC1; Asp118Asn) and ERCC2 (Lys751Gln). The correlation between these polymorphisms and the clinical outcome, including drug response, progression-free survival (PFS), overall survival (OS) and the incidence of peripheral neuropathy, were evaluated. Patients with the GSTP1-105 A/A genotype had poor responses to mFOLFOX6 treatment compared with those with the GSTP1-105 A/G and G/G genotypes (P=0.01). The median PFS of patients with the ERCC2-751 A/A genotype tended to be longer than that of patients with the ERCC2-751 A/C genotype (P=0.05). Patients with the TS-3′-UTR −6/−6 genotype had a significantly longer OS compared with patients with other genotypes (P=0.003). A statistically significant association between the incidence of peripheral neuropathy higher than grade 2 and the GSTP1-105 (P=0.03) and GSTM1 genotypes (P=0.02) was identified by multivariate logistic regression analyses. Results demonstrated that polymorphisms in GSTP1-105, ERCC2-751 and the 3′-UTR of TS may be a statistically significant predictors of clinical outcome. GSTP1-105 and GSTM1 genotypes may be useful markers of severe peripheral neuropathy in MCRC patients treated with 5-FU/oxaliplatin as first-line chemotherapy.

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

“…An important difference is that 6bp−/6bp− genotype frequencies described in these studies are higher than those found in our cohort of patients [14,44]. A comparison of VNTR genotype frequencies in similar studies from different populations shows similarities between Mexican and Caucasian populations from Italy, Hungary and Spain (2R/2R: 16%-24%, 2R/3R: 47%-49%, 3R/3R: 29%-35%), but noticeable differences with East Asian populations (2R/2R: 4%-5%, 2R/3R: 21%-29%, 3R/3R: 67%-73%) [14,15,25,45,46]. The low frequencies of the 2R allele in the last geographical group may explain the absence of significant association between the VNTR and clinical response in these populations [47].…”

“…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.…”

The XPD Lys751Gln Polymorphism has Predictive Value in Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy: a Systemic Review and Meta-analysis

“…By contrast, one article consisted of two independent studies, and studies included in this article were treated as separate studies (MartinezBalibrea et al, 2008). As a result, a total of 2286 CRC patients were enrolled in the 17 studies included in the pool analysis (Park et al, 2001;Stoehlmacher et al, 2004;Le Morvan et al, 2007;Ruzzo et al, 2007;Martinez-Balibrea et al, 2008;Pare et al, 2008;Lai et al, 2009;Boige et al, 2010;Chen et al, 2010;Etienne-Grimaldi et al, 2010;Farina Sarasqueta et al, 2011;Lamas et al, 2011;Chen et al, 2012;Gan et al, 2012;Li et al, 2012;Kumamoto et al, 2013). The selection procedure is shown in Figure 1, and the key patient characteristics are listed by study in Table 1.…”

Genetic variability of DNA repair mechanisms in chemotherapy treatment outcome of gastric cancer patients

“…Recently, several studies have focused on the association between ERCC1 and ERCC2 gene polymorphisms and clinical outcome of several kinds of cancers (Kumamoto et al, 2013;Nishina et al, 2013;Henríquez-Hernández et al, 2014;Li et al, 2014a;Sullivan et al, 2014;Zhou et al, 2015). However, only a few studies have reported on the role of ERCC1 and ERCC2 expression in the clinical outcome of patients with gastric cancer treated with chemotherapy (Yin et al, 2011;Li et al, 2013).…”