Ben Davidson1, Marianne Bjørnerem2, Arild Holth2, Ellen Hellesylt2, Thea E Hetland Falkenthal3, Vivi Ann Flørenes2. 1. 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. Electronic address: bend@medisin.uio.no. 2. Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway. 3. Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
Abstract
OBJECTIVE: To analyze the expression and clinical role of CHK1 and CHK2 in metastatic high-grade serous carcinoma (HGSC). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: To analyze the expression and clinical role of CHK1 and CHK2 in metastatic high-grade serous carcinoma (HGSC). METHODS: 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. RESULTS: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. CONCLUSIONS: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.
Authors: Sören A Weidemann; Charlotte Sauer; Andreas M Luebke; Christina Möller-Koop; Stefan Steurer; Claudia Hube-Magg; Franziska Büscheck; Doris Höflmayer; Maria Christina Tsourlakis; Till S Clauditz; Ronald Simon; Guido Sauter; Cosima Göbel; Patrick Lebok; David Dum; Christoph Fraune; Simon Kind; Sarah Minner; Jakob Izbicki; Thorsten Schlomm; Hartwig Huland; Hans Heinzer; Eike Burandt; Alexander Haese; Markus Graefen; Asmus Heumann Journal: BMC Cancer Date: 2019-10-12 Impact factor: 4.430