Association between glutathione-S-transferase GSTP1 genotypes, GSTP1 over-expression, and outcome in epithelial ovarian cancer

Abstract

Ovarian cancer accounts for the majority of deaths from gynaecological malignancy, and polymorphisms in genes encoding the glutathione-S-transferase (GST) GSTP1 detoxifying enzymes may lead to variation in detoxification of carcinogens. We describe a study involving 81 women with invasive epithelial ovarian cancer. A number of important clinical variables and outcome data were obtained. GSTP1 genotyping was undertaken using PCR-based techniques, and GSTP1 expression was quantified using immunohistochemistry (IHC). A Cox's proportional hazard regression model was used to analyze the effects on outcome. We also independently examined 11 women with borderline or low malignant potential (LMP) tumors using IHC only. The mean age of the women was 61.5 years ± 12 (1 SD) (range 36–88 years), the median overall survival was 26 months, and median progression free interval (PFI) 21 months. There was a significant association between GSTP1 (Val104/Val104) genotypes, and reduced survival (P= 0.05) and the GTP1 (Ile104/Val104)genotype appeared to have the best outcome (HR = 0.34,P= 0.045, 95% CI = 0.12–0.98). There was no significant association between the GSTP1 genotypes and any clinico-pathological parameters; there were also no associations between GSTP1 genotypes and response to postoperative chemotherapy. Specific nuclear GSTP1 over-expression was associated with less residual disease (P= 0.05); specific cytoplasmic GSTP1 over-expression with more favourable performance status (P= 0.014)). We found that 10/11 (91%) of the LMP (borderline) tumors over-expressed nuclear GSTP1 compared to only 52% of the invasive tumors (χ2(1)= 5.95,P= 0.015). There was no significant association between the level of GSTP1 expression and response to postoperative chemotherapy. The overall level of GSTP1 expression and the subcellular localization of GSTP1 expression were not associated with either survival or PFI. There was a significant association between the GSTP1 (Ile104/Ile104) genotypes and increased overall GSTP1 expression (P= 0.049), and the GSTP1 (Ile104/Val104) genotypes and reduced overall GSTP1 expression (P= 0.046). We speculate that GSTP1 Ile104/Val104genotypes are associated with improved outcome because the protein/enzyme, which is expressed, may provide a better balance between the effects of detoxification of carcinogens and the effects of metabolism of chemotherapy agents. In addition, over-expression of nuclear GSTP1 appears to be associated with more favorable ovarian tumor characteristics. In our preliminary study, we also reported a relationship between overall GSTP1 expression and certain GSTP1 genotypes. As far as we are aware, this is the first time that a relationship between the GSTP1 genotypes, GSTP1 expression and outcome has been described in ovarian cancer. Whether the genotype directly determines GSTP1 expression is at present unclear and the precise mechanism of this interaction is unknown.