- Top of page
- Materials and Methods
- Disclosure Statement
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. (Cancer Sci 2009)
Colorectal carcinoma (CRC) is one of the leading causes of cancer-related mortality in Taiwan and its incidence has increased steadily over the past few decades. Oxaliplatin is very effective in treating metastatic CRC patients,(1,2) and improves the disease-free survival of patients with stage II/III CRC.(3) Neuropathy is the major toxicity of oxaliplatin, and the incidence of oxaliplatin-induced severe neuropathy has varied from 12% to 18%.(3–5) Oxaliplatin-induced neuropathy includes an acute, transient peripheral nerve hyperexcitability,(6) and a chronic, dose-related, peripheral sensory neuropathy with symptoms similar to those caused by cisplatin.(7) Development of chronic neuropathy results in severe disturbance of neurologic functions. Therefore, identification of factors predictive of neurotoxicity to oxaliplatin treatment, including genes involved in the nucleotide excision repair (NER)(8,9) and detoxification pathways,(10) is of extreme interest.
Glutathione S-transferases (GST) are a multigene family of enzymes which catalyze the conjugation of glutathione to electrophilic xenobiotics to inactivate them, and thus prevent DNA damage and adduct formation.(11) At least five major classes of the GST superfamily have been identified,(10) among them, the GSTP1, GSTT1, and GSTM1 genotypes have been studies extensively for their influences in the inter-individual variations of outcome to chemotherapeutic agents.(12,13) The isoenzyme GSTP1 is highly expressed in human CRC tissues,(14) and participates in the detoxification of platinum drugs that may mediate the resistance to platinum-based chemotherapy. A single nucleotide polymorphism (A313G) in exon 5 of the GSTP1 gene causing isoleucine to valine substitution in the 105th amino acid (I105V) significantly decreases GSTP1 activity,(11) and has a profound impact on chemotherapy for CRC patients.(12,13)GSTP1 I105V polymorphism also predicts cumulative neuropathy in patients treated with docetaxel- as well as oxaliplatin-based chemotherapy,(15,16) but controversies exist. In addition, this polymorphism is associated with the susceptibility to several cancers.(17)
In addition to detoxification pathways, genetic polymorphisms in genes involved in DNA repair also attribute to resistance to oxaliplatin.(8,9) From a genetic viewpoint, in a multi-factorial disease, it is sometimes difficult with single polymorphisms in single genes to alter the extent of a physiologic or pathologic phenotype. Therefore, combined analysis of genes involved in the NER pathways, including ERCC1, XPD, and detoxification pathways, may more actually identify patients with maximal benefit, or toxicity, from oxaliplatin-based chemotherapy.
Ethnic differences have a profound influence on the response and toxicity to chemotherapeutic agents. Due to a higher prevalence of epidermal growth factor receptor mutations, gefitinib becomes very effective in Asian patients with non-small-cell lung cancer.(18) The UGT1A1*28 polymorphism is rare in Asian populations,(19) leading to decreased risk of severe neutropenia after being treated with irinotecan. Furthermore, Asian populations have a remarkably lower prevalence of ERCC1 codon 118 CT and XPD K751Q polymorphisms, which may affect platinum-based chemotherapy.(8,9) However, little is known about ethnic difference in GSTP1 I105V polymorphism and its impact on Asian CRC patients treated with oxaliplatin.
Based on these earlier findings, we propose that the GSTP1 I105V polymorphism may account for altered susceptibility and neuropathy to oxaliplatin-based chemotherapy in CRC patients. Ethnic difference of this polymorphism in Asian populations was analyzed, and combined analysis of the GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was conducted.
- Top of page
- Materials and Methods
- Disclosure Statement
In comparison with Caucasian populations,(12,16) a remarkably lower prevalence of the GSTP1 I105V polymorphism was noted in our patients (24.7%). Ethnic differences have a profound influence on chemotherapy for CRC patients. For example, the prevalence of homozygous triple-repeat polymorphism in TSER was twice as common in Chinese as in Caucasian subjects, which accounts for an impaired response to fluoropyrimidine regimens.(20) With regard to genes involved in the NER pathway, a remarkably lower prevalence of ERCC1 codon 118 C/T or T/T genotypes and XPD Gln751 allele variants have been found in Asian populations, which may account for an increased susceptibility to platinum-based chemotherapy.(8,9) It has been shown that Asian populations seem to have a lower prevalence of GSTP1 Val105 allele variants,(10) but the sample size was quite small (n = 11). In our study, a larger sample size (n = 166) was analyzed, and a remarkably lower percentage of Val105 allele variants (24.7%) was identified, compared to that in Caucasian populations.(12,16) These results implicated that Asian populations might have a better detoxification pathway. However, to date, no randomized study has been conducted to compare the outcome of FOLFOX treatment in different racial populations. Whether these polymorphisms may account for altered treatment outcome in Asian patients warrants further studies.
Altered expression of GST genes has been associated with different susceptibility to cancer.(22–24) For example, methylation of the regulatory sequences near the GSTP1, resulting in its inactivation, has been identified in the early stages of prostatic carcinogenesis.(22) Polymorphisms in GSTM1 and GSTT1 are associated with the susceptibility to colon cancer and age at onset,(23) and I105V polymorphism of the GSTP1 has been associated with susceptibility to testicular and bladder cancers.(17) Because I105V polymorphism of the GSTP1 is associated with reduced detoxification efficiency in comparison with the wild-type one,(11) a higher prevalence of the 105V allele variants might contribute to susceptibility in CRC. However, in the current study, there was no statistically difference between patients with CRC and control groups in different GSTP1 codon 105 genotypes, which was similar to a previous report.(24)
It has been reported that the ERCC1 codon 118 CT and XPD K751Q polymorphism results in a higher NER proficiency;(8,9) we proposed that these polymorphisms may have an influence in the development of neuropathy after treatment with oxaliplatin. But in the current study, patients with different ERCC1 codon 118 and XPD codon 751 genotypes had a similar incidence of severe neurotoxicity after treatment with FOLFOX-4 (P = 0.56 and 0.85, respectively). These results indicate that different NER proficiency and oxaliplatin metabolisms between nerve and tumor tissues might exist. Another explanation is that nerve cells are not in actively dividing status; therefore, oxaliplatin neurotoxicity may be mediated by a different mechanism than the platinum-DNA lesions. For example, oxalate, an oxaliplatin metabolite, may alter the properties of voltage-gated sodium channels or slow down the clearance of platinum compounds from the peripheral nervous system.(25)
We found that patients with GSTP1 Val105 allele variants had a significantly higher incidence of grade 3/4 cumulative neuropathy after treatment with FOLFOX-4 (Table 4). To date, in spite of the biochemical evidence that GSTs mediate the inactivation of platinum drugs, the association between polymorphisms in the GST genes and platinum-induced neurotoxicity remains controversial.(16,26,27) It has been shown that the Val105 allele variants of the GSTP1 were an unfavorable factor for developing neurotoxicity.(26) However, in another study, this polymorphism confers a decreased risk of developing severe cumulative neuropathy.(16) In another study, this polymorphism was not identified as having any correlation with oxaliplatin neurotoxicity.(27) In some cases, these results should be interpreted with caution because some studies were analyzed on a retrospective basis with very limited sample size. Furthermore, concurrent medications and environmental factors may also play important roles in inter-individual variability. Prospective studies with larger sample sizes and a homogenous population of patients treated with the same regimens are warranted in order to clarify this issue.
In the current study, patients with GSTP1 Val105 allele variants had a significantly higher response to FOLFOX-4 (56.1%vs 37.6%, P = 0.04) (Table 2) and longer progression-free and overall survivals (P < 0.01, Fig. 2), consistent with previous findings.(12,13) GSTP1 is directly involved in the detoxification of cisplatin by the formation of cisplatin-glutathione adducts,(28) indicating that GSTP1 plays a role in the acquisition of resistance to this platinum compound.(29) Patients with head and neck carcinoma with a lower level of intra-tumor GST expression also have a better response and survival to platinum-based treatment.(30) However, discrepancies existed in the association between GSTP1-105 variants and survival of CRC patients treated with oxaliplatin.(26,27) The authors explained that these controversies might result from the exertion of effects through a multistep cascade by most chemotherapeutic drugs. In addition, reduced enzymatic activity in Val105 allele variants leading to increased toxicities might have influenced patient survival.(26)
Interestingly, a better effect in predicting treatment outcome was found in combined analysis with genes involved in detoxification and NER pathways (Tables 2,3). In combined analysis with three risk genotypes, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, patients without risk genotypes had a remarkably higher response rate than those who had any one of the genotypes (P < 0.01, Table 2). Accordingly, remarkably longer progression-free and overall survivals (P < 0.01) are observed in patients without risk genotypes (HR = 5.73, Fig. 3). Because polymorphisms in genes involved in DNA repair also attributed to resistance to oxaliplatin,(8,9) combined analysis of several polymorphisms in genes involved in NER and detoxification pathways may be more predictive of treatment outcome of oxaliplatin-based chemotherapy.
Except for FOLFOX-4, the GSTP1 I105V polymorphism also has effects on other types of chemotherapy. In non-small-cell lung cancer patients, GSTP1 I105V polymorphism increases the response to platinum-based chemotherapy.(31) In acute myeloid leukemia patients, a significantly longer relapse-free, as well as overall survival, was found in patients with Val105 allele variants.(32) For gastric cancer patients treated with cisplatin plus 5-FU, carriage of the Val/Val genotype showed a significantly higher response rate and longer survival compared to those with at least one Ile allele.(33) However, for metastatic breast cancer patients treated with high-dose chemotherapy and autologous stem cell transplantation, the risks for disease progression and cancer specific death were higher in patients with AG or GG (Ile/Val or Val/Val) genotypes.(34) Whether this is due to pre-conditioning regimens that did not contain platinum drugs or simply due to different tumor type deserves further studies. With regard to irinotecan, this polymorphism was predictive of the response to irinotecan-based chemotherapy in metastatic CRC patients, with the Val105 allele variants being associated with a better outcome.(35)
In summary, we have demonstrated that Asian populations have a lower prevalence of I105V polymorphism in the GSTP1 gene. I105V polymorphism of the GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for increased response but more neurotoxicity to FOLFOX-4 treatment in Asian patients with metastatic CRC.