Polo-like kinase 3 and phosphoT273 caspase-8 are associated with improved local tumor control and survival in patients with anal carcinoma treated with concomitant chemoradiotherapy
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Franz Rödel1,6,7,*, Daniel Martin1,*, Christina Helmke2, Panagiotis Balermpas1,6,7, Emmanouil Fokas1,6,7, Ulrike Wieland3, Margret Rave-Fränk4, Julia Kitz5, Yves Matthess2,6,7, Monika Raab2, Klaus Strebhardt2,6,7, Claus Rödel1,6,7
1Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany
2Department of Gynecology, Goethe-University, Frankfurt am Main, Germany
3Institute of Virology, National Reference Centre for Papilloma- and Polyomaviruses, University of Cologne, Cologne, Germany
4Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany
5Department of Pathology, University Medical Center Göttingen, Göttingen, Germany
6German Cancer Research Center (DKFZ), Heidelberg, Germany
7German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany
*These authors contributed equally to this work
Franz Rödel, email: email@example.com
Keywords: anal carcinoma, Polo-like kinase 3, caspase-8, chemoradiotherapy, local control
Received: May 24, 2016 Accepted: July 13, 2016 Published: July 23, 2016
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.
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