Evaluation of nuclear NF-κB, transglutaminase2, and ERCC1 as predictors of platinum resistance in testicular tumors

ABSTRACT Purpose: Testicular germ cells tumor (TGCT) are associated with a high cure rate and are treated with platinum-based chemotherapy. However, a group of testicular cancer patients may have a very unfavorable evolution and insensitivity to the main therapeutic agent chemotherapy (CT) cisplatin. The aim of this study was to evaluate the risk of recurrence and overall survival related to the expression of nuclear factor kappa-B (NF-κB), transglutaminase 2 (TG2) and excision repair cross-complementation group 1 (ERCC1) in patients with TGCT treated with platinum combinations. Patients and Methods: A retrospective study was performed with TGCT patients treated with platinum-based chemotherapy. Immunohistochemical analysis was performed and the expression was correlated with clinical and laboratory data. Results: Fifty patients were included, the mean age was 28.4 years (18 to 45), and 76% were non-seminoma. All patients were treated with standard cisplatin, etoposide and bleomycin or cisplatin, and etoposide. Patient’s analyzed immunodetection for NF-κB, TG2, and ERCC1 were positive in 76%, 54% and 42%, respectively. Multivariate analysis identified that positive expressions to ERCC1 and NF-κB are independent risk factors for higher recurrence TGCT after chemotherapy (RR 2.96 and 3.16, respectively). Patients with positive expression of ERCC1 presented a poor overall survival rate for 10-year follow (p=0.001). Conclusions: The expression of ERCC1 and NF-κB give a worse prognosis for relapse, and only ERCC1 had an influence on the overall survival of TGCT patients treated with platinum-based chemotherapy. These may represent markers that predict poor clinical outcome and response to cisplatin.

摘要 目的：睾丸生殖细胞肿瘤（Testicular germ cells tumor, TGCT）治愈率较高，临床以铂类化疗为主要治疗手段。但部分睾丸癌患者预后极差，且对以顺铂为核心的一线化疗（chemotherapy, CT）不敏感。本研究旨在评估接受铂类联合化疗的TGCT患者中，核因子κB（nuclear factor kappa-B, NF-κB）、转谷氨酰胺酶2（transglutaminase 2, TG2）以及切除修复交叉互补基因1（excision repair cross-complementation group 1, ERCC1）的表达与复发风险及总生存期的相关性。
患者与方法：本研究纳入接受铂类化疗的TGCT患者，开展回顾性分析。采用免疫组化法检测相关蛋白表达，并将表达水平与临床及实验室数据进行关联分析。
结果：本研究共纳入50例患者，平均年龄28.4岁（18~45岁），其中76%为非精原细胞瘤患者。所有患者均接受标准化疗方案：顺铂+依托泊苷+博来霉素，或顺铂+依托泊苷。针对NF-κB、TG2及ERCC1的免疫检测阳性率分别为76%、54%及42%。多因素分析显示，ERCC1与NF-κB阳性表达均为TGCT患者化疗后复发的独立危险因素（相对危险度分别为2.96和3.16）。ERCC1阳性表达患者的10年总生存率更低（p=0.001）。
结论：ERCC1与NF-κB的阳性表达提示TGCT患者铂类化疗后复发预后更差，且仅ERCC1表达水平会影响此类患者的总生存期。上述指标或可作为预测TGCT患者不良临床结局及顺铂耐药性的生物标志物。