Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316 Oslo, Norway.
Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
Gynecol Oncol. 2018 Jul;150(1):136-142. doi: 10.1016/j.ygyno.2018.05.007. Epub 2018 May 24.
To analyze the expression and clinical role of CHK1 and CHK2 in metastatic high-grade serous carcinoma (HGSC).
HGSC effusions (n = 335; 280 peritoneal, 55 pleural) were analyzed for protein expression of total CHK1 and its phosphorylated forms p-ser317 and p-ser296, as well as total CHK2 and its phosphorylated form p-thr68 using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including chemotherapy response, and survival.
Carcinoma cells stained positive, predominantly at the nuclei, in the majority of cases (range 83-100% for the five antibodies), while expression in reactive mesothelial cells and tumor-associated macrophages was more variable. Total CHK1 (p = 0.037), p-CHK1ser317 (p = 0.001), p-CHK1ser296 (p = 0.002) and p-CHK2thr68 (p < 0.001) expression was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis. CHK1, p-CHK1ser296, p-CHK2thr68 and p-CHK1ser317 nuclear expression was positively related to expression of the checkpoint regulator WEE1, previously studied in this cohort (p = 0.003, p = 0.013, p = 0.001 and p = 0.01, respectively). Higher total CHK1 (p = 0.007), p-CHK1ser317 (p = 0.004), CHK2 (p = 0.01) and p-CHK2thr68 (p = 0.048) expression was significantly related to shorter overall survival in univariate analysis, and CHK1ser317 was an independent prognostic marker in multivariate analysis (p = 0.025). Higher p-CHK1ser317 (p = 0.03) and CHK2 (p = 0.034) expression was additionally associated with poor progression-free survival.
CHK1 and CHK2 and their activated forms are frequently expressed in HGSC effusions, with higher expression following exposure to chemotherapy, and their expression is related to survival.
分析有丝分裂检查点激酶 1（CHK1）和 CHK2 在转移性高级别浆液性癌（HGSC）中的表达及其临床作用。
分析了 335 例 HGSC 渗出液（280 例腹膜，55 例胸腔）中总 CHK1 及其磷酸化形式 p-ser317 和 p-ser296，以及总 CHK2 及其磷酸化形式 p-thr68 的蛋白表达情况，采用免疫组织化学法进行检测。分析其与临床病理参数的相关性，包括化疗反应和生存情况。
大多数情况下（五种抗体的阳性率范围为 83%-100%），癌细胞在细胞核中呈阳性染色，而反应性间皮细胞和肿瘤相关巨噬细胞的表达则更为多变。与诊断时获得的化疗前疾病相比，化疗后疾病复发时总 CHK1（p=0.037）、p-CHK1ser317（p=0.001）、p-CHK1ser296（p=0.002）和 p-CHK2thr68（p<0.001）的表达明显更高。CHK1、p-CHK1ser296、p-CHK2thr68 和 p-CHK1ser317 核表达与本队列中先前研究的检查点调节剂 WEE1 的表达呈正相关（p=0.003、p=0.013、p=0.001 和 p=0.01）。在单因素分析中，较高的总 CHK1（p=0.007）、p-CHK1ser317（p=0.004）、CHK2（p=0.01）和 p-CHK2thr68（p=0.048）表达与总生存时间较短显著相关，多因素分析中 CHK1ser317 是独立的预后标志物（p=0.025）。较高的 p-CHK1ser317（p=0.03）和 CHK2（p=0.034）表达与无进展生存期较差相关。
CHK1 和 CHK2 及其激活形式在 HGSC 渗出液中频繁表达，化疗后表达水平升高，其表达与生存有关。
