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

Abstract

// Franz Rödel 1, 6, 7, * , Daniel Martin 1, * , Christina Helmke 2 , Panagiotis Balermpas 1, 6, 7 , Emmanouil Fokas 1, 6, 7 , Ulrike Wieland 3 , Margret Rave-Fränk 4 , Julia Kitz 5 , Yves Matthess 2, 6, 7 , Monika Raab 2 , Klaus Strebhardt 2, 6, 7 , Claus Rödel 1, 6, 7 1 Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany 2 Department of Gynecology, Goethe-University, Frankfurt am Main, Germany 3 Institute of Virology, National Reference Centre for Papilloma- and Polyomaviruses, University of Cologne, Cologne, Germany 4 Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany 5 Department of Pathology, University Medical Center Göttingen, Göttingen, Germany 6 German Cancer Research Center (DKFZ), Heidelberg, Germany 7 German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany * These authors contributed equally to this work Correspondence to: Franz Rödel, email: franz.roedel@kgu.de Keywords: anal carcinoma, Polo-like kinase 3, caspase-8, chemoradiotherapy, local control Received: May 24, 2016      Accepted: July 13, 2016      Published: July 23, 2016 ABSTRACT 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/p16 INK4a 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/p16 INK4a 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.