The role of glutathione-S-transferase polymorphisms in ovarian cancer survival

https://doi.org/10.1016/j.ejca.2006.09.011Get rights and content

Abstract

Resistance to chemotherapy represents one of the most important causes of treatment failure in patients with ovarian cancer. Common polymorphisms in the glutathione-S-transferase (GSTM1, GSTP1 and GSTT1) family have been implicated in chemoresistence and ovarian cancer survival. In this study, we have analysed Australian women diagnosed with primary invasive epithelial ovarian cancer between 1985 and 1997, using DNA extracted from peripheral blood and archival uninvolved (normal) tissues. GSTP1 genotypes were determined using ABI Prism 7700 Sequence Detection System methodology (n = 448) and GSTT1 and GSTM1 genotypes using PCR-agarose methodology (n = 239). We observed a significant survival advantage among carriers of GSTP1 Ile105Val GG/GA genotype (HR 0.77, 95% confidence interval (CI) 0.61–0.99, p = 0.04) and a non-significant survival advantage among women who were homozygous for the GSTM1 and GSTT1 deletion variants. There was also evidence of an additive effect, with a stronger survival benefit in women carrying three low function GST genotypes (GSTM1 null, GSTT1 null and GSTP1 GA/GG) (HR 0.47, 95% CI 0.22–1.02). The results of this study, the largest to date, are consistent with a number of previous smaller studies which have also observed that reduced GST function was associated with better survival outcomes in patients with ovarian cancer.

Introduction

Survival following a diagnosis of ovarian cancer is universally poor. Current treatment includes aggressive surgery, removal of the tumour and resection of metastases with the goal of optimal surgical cytoreduction of tumour to <1 cm before the administration of platinum-based chemotherapy.1 Whilst the majority of patients achieve a favourable clinical response initially, most develop recurrent cancer and 5-year survival rates are as low as 20%.2 Despite the fact that residual disease is an important prognostic factor, some patients whose tumours are optimally debulked develop de novo resistance to chemotherapy and have poor survival.3 At the other extreme, a small minority of women whose tumours are suboptimally debulked are sensitive to chemotherapy and never relapse.4 This range of outcomes is intriguing and may be attributable, at least in part, to sequence variations in genes encoding drug metabolism enzymes, such as common polymorphisms in the glutathione-S-transferase M1, T1 and P1 enzymes (encoded by GSTM1, GSTT1 and GSTP1, respectively).5

The GST enzymes catalyse the conjugation of glutathione with a variety of electrophilic compounds, including cytotoxic agents.6, 7 Three of the GST genes GSTP1, GSTM1 and GSTT1 have been found to have functional polymorphisms that are frequently present in the general population.8, 9 These polymorphisms either decrease or abolish GST enzyme activity. A single nucleotide substitution (A > G) at position 313 of the GSTP1 gene, which results in replacement of isoleucine with valine at amino acid position 104, substantially diminishes GSTP1 activity, probably due to decreased enzyme stability.10, 11, 12 Inherited homozygous deletions of the GSTT1 and GSTM1 gene lead to the complete absence of enzyme activity.13, 14, 15 There is some evidence that GST polymorphisms may play a role in the response to treatment and survival from some cancers16, 17, including cancer of the ovary.5, 18, 19, 20 In particular, GSTP1 has been shown to interact with platinum-based compounds21 and glutathione-conjugated platinum can be quickly effluxed from cells.22 Thus, it has been suggested that high GST activity may result in more rapid drug metabolism that diminishes the cytotoxic effects of chemotherapy on tumour cells, and hence be associated with poor treatment response and worse survival.18

GSTP1 expression has been shown to be associated with less favourable response and survival in some studies19, 20, 23 although no such relationship has been detected in other studies.24, 25 Many of these studies have however been small, and adjustment for clinical factors has varied.

Given the biochemical evidence that the GST enzymes are involved in the detoxification of platinum based cytotoxic agents, we hypothesised that decreased activity of the GST detoxification pathway (due to null or reduced expression of particular GST enzymes) could make some ovarian cancers more sensitive to chemotherapy and hence be associated with better survival. Therefore, we analysed common polymorphisms in the GSTP1, GSTM1, and GSTT1 in a large group of women diagnosed with ovarian cancer between 1985 and 1997 to determine whether the presence of one or more of these polymorphisms was associated with survival.

Section snippets

Subjects

This study included 454 women, aged 18–80 years diagnosed with primary incident invasive epithelial ovarian cancer between 1985 and 1997. Just over two thirds of the women (n = 296 [67%]) had participated in an Australian population based case-control study, the Survey of Women’s Health (SWH) between 1990 and 1993. The methods have been described previously.26 Briefly, these women were ascertained through major gynaecology–oncology treatment centres in the three most populous Australian states:

Results

Among the 454 women with invasive epithelial ovarian cancer, 288 (63%) had died from the disease during the follow-up period. The crude 5-year survival for these women was 44% (standard error (SE) = 2%). As expected a number of the clinical and pathological factors were clearly associated with survival in the crude analyses, but in a multifactorial model the only factors that remained significant were older age at diagnosis, late FIGO stage, histological subgroup and higher histologic grade (

Discussion

This study suggests that genetic variability in GST is independently associated with survival in a large cohort of patients with invasive epithelial ovarian cancer who mostly received platinum based chemotherapy. Patients who carried the null deletions in the GSTT1 and GSTM1 genes had moderate survival benefits compared with patients with high expression, and lower function GSTP1 genotypes also conferred a survival advantage. We also found an inverse, but statistically non-significant,

Conflict of interest statement

None declared.

Acknowledgements

We are grateful to the physicians, surgeons and oncologists who endorsed this project, and the many women who participated in this research. We thank Xiaoqing Chen for assistance with genotyping, and Lee Tripcony for assistance with data retrieval for this project.

Sources of support: This study was supported in part by a grant from the Mayne Bequest Fund, University of Queensland. Initial funding to recruit the cases for the Survey of Women’s Health was obtained from the National Health &

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