Howells R E J, Dhar K K, Hoban P R, Jones P W, Fryer A A, Redman C W E, Strange R C
Department of Obstetrics and Gynaecology, North Staffordshire Hospital, Stoke-on-Trent, Staffordshire, UK.
Int J Gynecol Cancer. 2004 Mar-Apr;14(2):242-50. doi: 10.1111/j.1048-891X.2004.014207.x.
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 (Val(104)/Val(104)) genotypes, and reduced survival (P = 0.05) and the GTP1 (Ile(104)/Val(104)) 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 (chi(2) ((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 (Ile(104)/Ile(104)) genotypes and increased overall GSTP1 expression (P = 0.049), and the GSTP1 (Ile(104)/Val(104)) genotypes and reduced overall GSTP1 expression (P = 0.046). We speculate that GSTP1 Ile(104)/Val(104) genotypes 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.
卵巢癌是妇科恶性肿瘤死亡的主要原因，编码谷胱甘肽 - S - 转移酶（GST）的GSTP1解毒酶基因的多态性可能导致致癌物解毒的差异。我们描述了一项涉及81例浸润性上皮性卵巢癌女性的研究。获得了一些重要的临床变量和结局数据。使用基于PCR的技术进行GSTP1基因分型，并使用免疫组织化学（IHC）对GSTP1表达进行定量。采用Cox比例风险回归模型分析对结局的影响。我们还仅使用IHC独立检查了11例交界性或低恶性潜能（LMP）肿瘤的女性。这些女性的平均年龄为61.5岁±12（1个标准差）（范围36 - 88岁），总生存期中位数为26个月，无进展生存期（PFI）中位数为21个月。GSTP1（Val(104)/Val(104)）基因型与生存率降低之间存在显著关联（P = 0.05），而GTP1（Ile(104)/Val(104)）基因型似乎具有最佳结局（HR = 0.34，P = 0.045，95%置信区间 = 0.12 - 0.98）。GSTP1基因型与任何临床病理参数之间均无显著关联；GSTP1基因型与术后化疗反应之间也无关联。特异性核GSTP1过表达与残留疾病较少有关（P = 0.05）；特异性细胞质GSTP1过表达与更好的体能状态有关（P = 0.014）。我们发现，11例LMP（交界性）肿瘤中有10例（91%）核GSTP1过表达，而浸润性肿瘤中只有52%过表达（卡方检验((1)) = 5.95，P = 0.
