title: 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: 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.
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: Department of Gynecology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Helmke
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Balermpas
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: Institute of Virology, National Reference Centre for Papilloma- and Polyomaviruses, University of Cologne, Cologne, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wieland
authors.affiliation: Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Rave-Fränk
authors.affiliation: Department of Pathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kitz
authors.affiliation: Department of Gynecology, Goethe-University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany.
authors.forename: Yves
authors.initials: Y
authors.lastname: Matthess
authors.affiliation: Department of Gynecology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Raab
authors.affiliation: Department of Gynecology, Goethe-University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK) partnersite: Frankfurt, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001005:Anus Neoplasms / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D053181:Caspase 8 / Q000378:metabolism*; D059248:Chemoradiotherapy; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D030361:Papillomavirus Infections / Q000150:complications / Q000628:therapy / Q000821:virology; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins; D014443:Tyrosine / Q000378:metabolism; D000097868:Polo-like Kinases
chemical_list: D053181:Caspase 8; D004279:DNA, Viral; D005472:Fluorouracil; D016685:Mitomycin; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; C486256:PLK3 protein, human; D000097868:Polo-like Kinases
keywords: anal carcinoma; caspase-8; chemoradiotherapy; local control; Polo-like kinase 3