DARPP32, STAT5 and STAT3 mRNA Expression Ratios in Glioblastomas are Associated with Patient Outcome
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RESEARCH
DARPP32, STAT5 and STAT3 mRNA Expression Ratios in Glioblastomas are Associated with Patient Outcome Despina Televantou & George Karkavelas & Prodromos Hytiroglou & Sofia Lampaki & George Iliadis & Panagiotis Selviaridis & Konstantinos S. Polyzoidis & George Fountzilas & Vassiliki Kotoula
Received: 12 July 2012 / Accepted: 7 November 2012 / Published online: 20 December 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Based on recent developments in glioblastoma subtyping, we examined DARPP32 (PPP1R1B), a neuronal marker against STAT5 and STAT3 that are pro-oncogenic in glioblastoma. mRNA ratios of DARPP32, STAT1, STAT3, STAT5A and STAT5B were assessed in routinely diagnosed gliomas s including a series of glioblastomas from patients (n067) treated with chemoradiotherapy (temozolomide), out of which 88 % had sequencing validated IDH-negative disease. DARPP32/STAT1 (p00.0007), DARPP32/STAT3 (p0 0.0004) and DARPP32/STAT5B (p00.0039) ratios were significantly higher in grade II and III as compared to grade IV tumours. The same high ratios were also associated with absence of immunohistochemically assessed AKT/PKB phosphorylation and survivin protein expression. High DARPP32/ STAT3, DARPP32/STAT5B, and STAT5B/STAT3 ratios were associated with longer patient progression free (PFS) and D. Televantou : G. Karkavelas : P. Hytiroglou : V. Kotoula (*) Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, University Campus, 54006 Thessaloniki, Greece e-mail: [email protected] S. Lampaki : G. Fountzilas Department of Medical Oncology, “Papageorgiou” General Hospital, Thessaloniki, Greece G. Iliadis Department of Radiation Oncology, “Papageorgiou” General Hospital, Thessaloniki, Greece P. Selviaridis : K. S. Polyzoidis 1st Neurosurgical Department, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
overall survival (OS). Upon multivariate analysis, total/subtotal removal of the tumour (HR:0.431; 95%CI:0.241–0.771, Wald p 00.005), high DARPP32/STAT5B (HR:0.341; 95%CI:0.169–0.690; Wald p00.003) and STAT5B/STAT3 mRNA ratios (HR:0.480; 95%CI:0.280–0.824; Wald p0 0.008) were independent favorable parameters for prolonged PFS. Extent of surgery (HR:0.198; 95%CI:0.101–0.390; p< 0.001) and high DARPP32/STAT5A ratios (HR:0.320; 95%CI:0.160–0.638, p00.001) were independently predictive for longer OS. The presented approach is applicable for prospective validation and appears promising towards an effective glioblastoma patient stratification in addition to IDH mutations. These data may contribute to understanding the biology of gliomas with respect to their potential neuronal characteristics and justify STAT-inhibiting therapeutic interventions in the same tumour system. Keywords Glioblastoma subtyping . IDH-negative disease . DARPP32 . STAT3 . STAT5A . STAT5B . Gene expression . Survivin
Introduction Diffuse gliomas, i.e., tumours with astrocytic, oligodendrocytic, ependymal or mixed cell characteristics, are the most common
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