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 (<i>TS</i>), methylenetetrahydrofolate reductase (<i>MTHFR</i>; Ala677Val), glutathione S-transferase π (<i>GSTP1</i>; IIe105Val), GST θ1 (<i>GSTT1</i>; deletion) and GST μ1 (<i>GSTM1</i>; deletion) and the two DNA-repair genes, excision repair cross-complementing-1 (<i>ERCC1</i>; Asp118Asn) and <i>ERCC2</i> (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 <i>GSTP1</i>-105 A/A genotype had poor responses to mFOLFOX6 treatment compared with those with the <i>GSTP1</i>-105 A/G and G/G genotypes (P=0.01). The median PFS of patients with the <i>ERCC2-</i>751 A/A genotype tended to be longer than that of patients with the <i>ERCC2</i>-751 A/C genotype (P=0.05). Patients with the <i>TS</i>-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 <i>GSTP1</i>-105 (P=0.03) and <i>GSTM1</i> genotypes (P=0.02) was identified by multivariate logistic regression analyses. Results demonstrated that polymorphisms in <i>GSTP1</i>-105, <i>ERCC2</i>-751 and the 3'-UTR of <i>TS</i> may be a statistically significant predictors of clinical outcome. <i>GSTP1</i>-105 and <i>GSTM1</i> genotypes may be useful markers of severe peripheral neuropathy in MCRC patients treated with 5-FU/oxaliplatin as first-line chemotherapy.