Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS) – novel predictors for response and survival in gastric cancer patients

Abstract

To evaluate the predictive value of a panel of gene polymorphisms involved in metabolism of 5-FU and cisplatin on clinical outcome in advanced gastric cancer patients. A total of 52 patients were enrolled in this study. DNA was extracted from paraffin-embedded tumour specimen. Genotypes were determined using PCR-RFLP. Median survival time was 6.0 months (95% CI 3.9;8.1). Overall response rate was 26%. Patients possessing the glutathione S-transferase P1-105 Valine/Valine (GSTP1-105VV) genotype showed a response rate of 67% compared to 21% in patients harbouring at least one GSTP1-105 Isoleucine (GSTP1-105I) allele (P ¼ 0.038). GSTP1-105VV patients demonstrated a significant superior median survival time of 15.0 months (95% CI 7.8;22.0) compared to 6.0 months (95% CI 5.1;7.0) in patients with at least one GSTP1-105I allele (P ¼ 0.037). Patients possessing a favourable thymidylate synthase (TS) genotype (2R/2R, 2R/3RC, 3RC/3RC) experienced a superior survival time of 10.2 months (95% CI 5.1;15.3) compared to 6.0 months (95% CI 5.0;7.0) in patients with unfavourable TS genotypes (P ¼ 0.099). Patients harbouring the GSTP1-105II genotype and one of the unfavourable TS genotypes showed an inferior median survival time of 6.0 months (95% CI 3.9;8.1) compared to 11 months (95% CI 6,23;15,77) in patients with either GSTP1-105VV or a favourable TS genotype (P ¼ 0.044). Testing for TS and GSTP1 polymorphisms may allow identification of gastric cancer patients who will benefit from 5-FU/cisplatin chemotherapy, sparing others the side effects of this chemotherapy.

Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population

“…It was in agreement with the previous studies of colorectal and breast cancer. 27,29 However, Goekkurt 30 and Stoehlmacher 31 showed that GSTP1-105 G/G genotype predicted superior survival in gastric cancer patients and colorectal cancer patients, respectively. In this study, GSTP1-105 polymorphism did not play a significant role in the prediction of clinical outcome, perhaps due to the rare number of patients who had the G/G genotype, indicating that ethnic background eliminated race-specific variation in the distribution of genotypes in GSTP1.…”

GSTP1 Ile105Val polymorphism correlates with progression-free survival in MCRC patients treated with or without irinotecan: a study of the Dutch Colorectal Cancer Group

“…We demonstrate that, as opposed to the overall study population, Ile/Ile carriers do not benefit from the addition of irinotecan to CAP. A number of studies have been conducted to investigate the GSTP1 polymorphism with respect to the treatment effects of other chemotherapeutic compounds, such as busulfan (Zwaveling et al, 2008), melphalan (Kuhne et al, 2008), cyclophosphamide (Zhong et al, 2006), oxaliplatin (Stoehlmacher et al, 2002;Ruzzo et al, 2007) and cisplatin (Goekkurt et al, 2006). In vitro data (Goto et al, 2002) have shown that the presence of GSTP1 in the cell nucleus protects the cell from irinotecan-induced apoptosis.…”

Predictive Role of Glutathione-S-transferase Gene Polymorphisms in Risk and Prognosis of Hepatocellular Carcinoma

“…Genotypic and phenotypic variation in GST activity has been noted, and is thought to affect risk and prognosis in several cancers (Wiencke et al, 1990;Pemble et al, 1994;Hayes and Pulford, 1995;Dalhoff et al, 2005;Yang et al, 2005;Goekkurt et al, 2006;Reszka et al, 2006;Shiga et al, 2006). The Single nucleotide polymorphisms (SNPs) of GST genes induced the different expression of the gene product, and GSTM1, GSTT1 and GSTP1 genotypes have been hypothesized to affect the risk of HCC (Zhang et al, 2005;White et al, 2008;Giera et al, 2010), and response to chemotherapy (Ott et al, 2008;Tahara et al, 2011).…”