title: Mesenchymal subtype of glioblastomas with high DNA-PKcs expression is associated with better response to radiotherapy and temozolomide.
abstract: A better understanding of the relationship between glioblastomas molecular subtypes and radio-chemotherapy is needed for the development of individualized strategies. In this study, we aimed to assess whether non-homologous end-joining (NHEJ) protein expression is associated and could predict responses to treatment of mesenchymal (MES) and proneural (PN) subtypes. Tumors from 122 patients with a glioblastoma treated at the University Hospital of Poitiers between 2002-2013 by an association of radiotherapy and temozolomide were collected. Among these tumors, 80 were suitable for in situ analysis and were included in TissueMicroArray. The expression of DNA-PKcs, Ku70, Ku80 and CD44, Olig2 (respectively surrogate markers of MES and PN subtypes) were evaluated by immunohistochemistry. The median survival of patients with high and low CD44 expression was 11.9 months (95% CI 7.7-14) and 19.1 months (95% CI 15.2-22.4) respectively (p = 0.008). Median survival of patients with high and low DNA-PKcs levels was 20.0 months (95% CI 15.2-25.3) and 12.9 months (95% CI 9.9-19.5) respectively (p = 0.036). High levels of Olig2, Ku70 and Ku80 tended to be associated with better overall survival but no significant differences were found. Overall survival of class I patients (CD44+ and DNA-PKcs+) was longer than class II (CD44+ and DNA-PKcs- or CD44- and DNA-PKcs+) and class III (CD44- and DNA-PKcs-), (p = 0.005 and 0.003 respectively). High levels of CD44 and DNA-PK are associated with a better survival and better response to radiotherapy and temozolomide and could establish prognosis classes by predicting survival and response to therapy for GBMs patients.
authors.affiliation: CHU de Poitiers Department of Cancer Biology, Université de Poitiers, Poitiers, France.|CHU de Poitiers Department of Radiotherapy, Université de Poitiers, Poitiers, France.
authors.forename: Baptiste
authors.identifier: http://orcid.org/0000-0003-0397-6677
authors.initials: B
authors.lastname: Pinel
authors.affiliation: CHU de Poitiers Department of Pathology, Université de Poitiers, Poitiers, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Duchesne
authors.affiliation: CHU de Poitiers Department of Pathology, Université de Poitiers, Poitiers, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Godet
authors.affiliation: CHU de Poitiers Department of Pathology, Université de Poitiers, Poitiers, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Milin
authors.affiliation: CHU de Poitiers Department of Radiotherapy, Université de Poitiers, Poitiers, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Berger
authors.affiliation: CHU de Poitiers Department of Neurosurgery, Université de Poitiers, Poitiers, France.|INSERM U-1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, Poitiers, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Wager
authors.affiliation: CHU de Poitiers Department of Cancer Biology, Université de Poitiers, Poitiers, France. l.karayan-tapon@chu-poitiers.fr.|INSERM U-1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, Poitiers, France. l.karayan-tapon@chu-poitiers.fr.|Department of Cancer Biology, University Hospital of Poitiers, 86021, Poitiers, France. l.karayan-tapon@chu-poitiers.fr.
authors.forename: Lucie
authors.initials: L
authors.lastname: Karayan-Tapon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D000072200:Ku Autoantigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2 / Q000378:metabolism; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D000077204:Temozolomide; D046888:Tissue Array Analysis
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018960:Hyaluronan Receptors; D009687:Nuclear Proteins; C405708:OLIG2 protein, human; D000076104:Oligodendrocyte Transcription Factor 2; D003606:Dacarbazine; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D000072200:Ku Autoantigen; D000077204:Temozolomide
keywords: CD44; DNA-PKcs; Glioblastoma; Overall survival