DNA damage repair proteins, HSP27 and phosphorylated-HSP90alpha as predictive/prognostic biomarkers of platinum-based cancer chemotherapy: An exploratory study

Platinum analogues are commonly used for cancer treatment. There is increasing interest in finding biomarkers which could predict and overcome resistance, because to date there is no reliable predictive/prognostic marker for these compounds. Here we studied the immunohistochemical (IHC) expression of proteins involved in DNA damage response and repair (γH2AX, 53BP1, ERCC1, MLH1, and MSH2) in primary tumor tissues from patients treated with platinum-based chemotherapy. Levels and localization of HSP27 and phospho-(Thr5/7)-HSP90α (p-HSP90α) were also determined. The implications in clinical response, disease free survival (DFS) and overall survival (OS) were analysed. High γH2AX and 53BP1 expressions were associated with poor clinical response. Nuclear p-HSP90α, as well as nuclear absence and low cytoplasmic expression of HSP27 correlated with good response. Patients with high γH2AX and high cytoplasmic HSP27 expressions had shorter OS and DFS. MLH1, MSH2 or ERCC1 were not associated with clinical response or survival. We report the potential utility of p-HSP90α, HSP27, γH2AX and 53BP1 as predictive/prognostic markers for platinum-based chemotherapy. We present the first study that evaluates the predictive and prognostic value of p-HSP90α in primary tumors. Our research opens new possibilities for clinical oncology and shows the usefulness of IHC for predicting chemotherapy response and prognosis in cancer.

铂类化合物在癌症治疗中应用广泛。目前，对寻找能够预测和克服耐药性的生物标志物的兴趣日益浓厚，因为迄今为止，尚无可靠的预测/预后标志物可用于这些化合物。在本研究中，我们探讨了经铂类化疗治疗的患者的原发性肿瘤组织中，参与DNA损伤响应和修复的蛋白（如γH2AX、53BP1、ERCC1、MLH1和MSH2）的免疫组化（IHC）表达情况。同时，还确定了HSP27和磷酸化（Thr5/7）-HSP90α（p-HSP90α）的水平及定位。分析了这些指标在临床反应、无病生存期（DFS）和总生存期（OS）方面的意义。高γH2AX和53BP1表达与不良的临床反应相关。核p-HSP90α、核缺失和低细胞浆HSP27表达与良好的反应相关。γH2AX和细胞浆HSP27表达均高的患者，其OS和DFS均较短。MLH1、MSH2或ERCC1与临床反应或生存期无显著关联。我们报道了p-HSP90α、HSP27、γH2AX和53BP1作为铂类化疗预测/预后标志物的潜在应用价值。我们呈现了首项评估p-HSP90α在原发性肿瘤中预测和预后价值的实验研究。我们的研究为临床肿瘤学开辟了新的可能性，并展示了免疫组化在预测化疗反应和癌症预后方面的实用性。