Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma

Abstract

Glutathione S-transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum-based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first-line FOLFOX-4. Combined analysis of GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX-4 (56.1%vs 37.6%, P = 0.04), and a longer progression-free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, had significantly longer progression-free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX-4 treatment.

Figure 1

Representative PCR‐restriction fragment length polymorphism (RFLP) patterns of different glutathione S‐transferase P1 (GSTP1) codon 105 genotypes examined by patients’ blood samples. Genomic DNA obtained from patients’ leukocytes was subjected to PCR amplification using 5′‐ACC CCA GGG CTC TAT GGG AA‐3′ and 5′‐TGA GGG CAC AAG AAG CCC CT‐3′ as forward and reverse primers, respectively. PCR products after being digested by BsmAI were separated by agarose gel electrophoresis. Lanes 1 and 4 represent Val/Val; lanes 2, 3, 8, and 9 represent Ile/Val; lanes 5, 6, and 7 represent Ile/Ile. Lane UC indicates PCR product that has not been digested.

Figure 2

Patients with glutathione S‐transferase P1 (GSTP1) codon 105 Ile→Val polymorphism have significantly longer progression‐free and overall survivals after being treated with FOLFOX‐4. (a) Progression‐free survival curves of 166 patients with GSTP1‐105 Ile/Ile (wild type) or Ile/Val, Val/Val genotypes are plotted by Kaplan–Meier method (P < 0.01, log‐rank test). (b) A similar method has been used to plot overall survival curves of patients with different GSTP1 codon 105 genotypes (P < 0.01).

Figure 3

Patients without risk genotypes (GSTP1‐105 Ile/Ile, ERCC1‐118 C/T or T/T, and XPD‐751 Lys/Gln) have a significantly longer progression‐free as well as overall survival time after treatment with FOLFOX‐4. (a) Progression‐free survival curves of 166 patients with or without any risk genotype plotted by Kaplan–Meier method (P < 0.01, log‐rank test). (b) A similar method has been used to plot overall survival curves of patients with or without any risk genotype (P < 0.01).