2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia.
Translation Research Unit, National Cancer Institute, Comenius University, Bratislava, Slovakia.
Neoplasma. 2024 Aug;71(4):374-386. doi: 10.4149/neo_2024_240609N249.
Cisplatin-based chemotherapy is the mainstay in the treatment of germ cell tumors (GCTs). Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by chemotherapy and are thus implicated in developing treatment resistance. This study aimed to assess the expression level of GST mu 1 (GSTM1) and its association with treatment outcomes in patients with GCT. This translational study included tumor specimens from 207 patients with newly diagnosed GCTs, as well as cisplatin-sensitive GCT cell line xenografts and their resistant variants for all histological variants of GCTs. GSTM1 expression was detected by reverse transcription-quantitative PCR and immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method. GSTM1 expression was correlated with patient/tumor characteristics and treatment outcomes. The highest GSTM1 expression was observed in seminoma, followed by choriocarcinoma, embryonal carcinoma, and yolk sac tumor, while the lowest was observed in teratoma (p<0.0001). There was no association between GSTM1 expression in tumor tissue and patient/tumor characteristics. The low GSTM1 expression was associated with significantly better relapse-free survival compared with high GSTM1 (HR=0.50, 95% CI 0.23-1.09, p=0.03) but not overall survival (HR=0.61, 95% CI 0.24-1.54, p=0.22). Multivariate analysis showed that the prognostic value of GSTM1 was independent of the International Germ Cell Cancer Collaborative Group (IGCCCG) score. These data revealed the prognostic value of GSTM1 in GCTs, with a high GSTM1 expression associated with worse outcomes, suggesting that GSTM1 could be responsible, in part, for treatment resistance in GCTs.
基于顺铂的化疗是生殖细胞肿瘤 (GCT) 治疗的主要手段。谷胱甘肽 S-转移酶 (GSTs) 是多态酶，可催化烷化剂、铂化合物和化疗形成的自由基与谷胱甘肽的结合，因此与产生治疗耐药性有关。本研究旨在评估 GST mu 1 (GSTM1) 的表达水平及其与 GCT 患者治疗结果的关系。这项转化研究包括 207 例新诊断的 GCT 患者的肿瘤标本，以及所有 GCT 组织学变体的顺铂敏感 GCT 细胞系异种移植物及其耐药变体。使用单克隆抗体通过逆转录定量 PCR 和免疫组织化学检测 GSTM1 的表达，并用乘法快速评分 (QS) 方法评分。GSTM1 的表达与患者/肿瘤特征和治疗结果相关。GSTM1 的表达在精原细胞瘤中最高，其次是绒毛膜癌、胚胎癌和卵黄囊瘤，而在畸胎瘤中最低 (p<0.0001)。肿瘤组织中 GSTM1 的表达与患者/肿瘤特征之间没有关联。低 GSTM1 表达与高 GSTM1 相比，无复发生存率显著提高 (HR=0.50，95%CI 0.23-1.09，p=0.03)，但总生存率无差异 (HR=0.61，95%CI 0.24-1.54，p=0.22)。多变量分析显示，GSTM1 的预后价值独立于国际生殖细胞癌协作组 (IGCCCG) 评分。这些数据揭示了 GSTM1 在 GCT 中的预后价值，高 GSTM1 表达与较差的结局相关，表明 GSTM1 可能部分导致 GCT 的治疗耐药性。
