Association analysis of glutathione‐S‐transferase P1 (GSTP1) polymorphism with urothelial cancer susceptibility and myelosuppression after M‐VAC chemotherapy

Abstract

Aim: Glutathione-S-transferase P1 (GSTP1) detoxifies a wide range of endogenous and exogenous carcinogens and anticancer agents such as cisplatin and doxorubicin. The aim of this study was to examine the association between GSTP1 polymorphism and both urothelial cancer susceptibility and adverse events of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy in Japanese urothelial cancer patients. Methods: This cohort consisted of 179 urothelial cancer patients and 225 healthy controls matched for age and sex. GSTP1 Ile105Val polymorphism was identified by direct sequencing methods. Furthermore, the association of GSTP1 polymorphism and adverse events of M-VAC chemotherapy was investigated. Results: A similar frequency of GSTP1 Ile105Val allele was observed in the urothelial cancer patients and in the control group. However, when the 46 patients who underwent systemic M-VAC chemotherapy were investigated , significantly more severe toxicity in leukocytopenia (P = 0.044, odds ratio +•, 95% confidence interval 0.9203-+•) and a prolonged duration of G-CSF administration (P = 0.013, odds ratio 8.625, 95% confidence interval 1.390-89.98) were observed in patients with the Val allele in comparison to those with the Ile allele. Conclusions: The GSTP1 Ile105Val polymorphism was not found to be significantly associated with urothelial cancer susceptibility but it may be associated with myelosuppressive adverse events in M-VAC chemotherapy. The 105Val might therefore be a useful marker for predicting myelosuppression in M-VAC chemotherapy.Key words: GSTP1, M-VAC, neutrocytopenia, polymorphism, urothelial cancer. IntroductionGlutathione-S-transferases (GST) are a family of five classes of detoxification enzymes that are involved in the metabolism of a wide variety of potentially carcinogenic compounds and anticancer agents. 1-5Tobacco smoking is a major risk factor for bladder cancer and it is responsible for about 45% of all bladder cancers. 6,7 One of the most important classes of bladder carcinogens in tobacco smoking is benzo(a)pyrenes, and they are detoxified by GSTP1,8 which is located on chromosome 11q13.2 GST polymorphic variances can affect the function of these enzymes and they have also been shown to be associated with differences in clinical phenotypes. A single nucleotide polymorphism (SNP) in the coding sequence at codon 105 (Ile105Val) of GSTP1 was found to result in a reduced enzymatic activity in vitro. 9 It seems reasonable that a decreased detoxification capacity by reduced enzymatic activity may increase susceptibility to cancer.Several studies have examined the GSTP1 Ile105Val polymorphism in oral, breast and prostate cancer susceptibility.3,10-14 However, the findings remain controversial in bladder and urothelial cancer. Some studies reported a positive correlation between this polymorphism and bladder cancer, [15][16][17] while other studies found no correlation between this polymorphism and urothelial cancers. 18 Moreover, meta-analyses on Spanish patients found a significant as...

Prognostic role of glutathione S-transferase polymorphisms in acute myeloid leukemia

“…36 In a group of 46 patients with bladder cancer, individuals with the GSTP1*Val allele showed a higher myelotoxicity after the chemotherapy regimen M-VAC. 37 Our finding of a reduced hematoxicity after chemotherapy in AML patients with the GSTP1*105Val allele, based on the analysis of 832 treatment cycles from 307 patients, appears to be in contrast with these data. One hypothesis could be that different from solid tumors, residual hematopoiesis is severely impaired in AML at diagnosis, and an improved eradication of leukemic cells after chemotherapy might result in a more rapid restoration of normal hematopoiesis.…”

GSTP1 Ile105Val Polymorphism and Prostate Cancer Risk: Evidence from a Meta-Analysis

“…GSTP1, which is involved in the detoxification of carcinogenic polycyclic aromatic hydrocarbons, has been investigated extensively in relation to different types of cancer, such as breast cancer [57], [58], bladder cancer [59], [60], oesophageal cancer [61], [62], and so on [5]. Previous results of the studies on the association of GSTP1 Ile105Val polymorphism with prostate cancer risk were inconclusive.…”

Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

“…Some investigations have shown that patients with G/G genotype present less toxicity (Oldenburg et al, 2007a , b ; Goekkurt et al, 2009 ; Kim et al, 2009 ) with more survival (Goekkurt et al, 2006 ; Ruzzo et al, 2006 ; Ji et al, 2013 ) and better therapy response (Sun et al, 2010 ; Yang et al, 2012 ). On the other hand, the G allele has been associated with a risk of myelosuppression, polyneuropathy, and toxicity (Yokomizo et al, 2007 ; Joerger et al, 2012 ; Windsor et al, 2012 ; Rednam et al, 2013 ). In ovarian cancer, the A allele is related to better PFS and OS (Khrunin et al, 2010 ).…”