title: High levels of polo-like kinase 1 and phosphorylated translationally controlled tumor protein indicate poor prognosis in neuroblastomas.
abstract: Despite multimodality treatment, the long-term survival of high-risk patients with neuroblastomas is below 50%. New anti-mitotic drugs against targets, such as polo-like kinase 1 (PLK1), are being evaluated in early phase clinical trials. PLK1 phosphorylates the translationally controlled tumor protein (TCTP). We investigated the expression of PLK1 and the phosphorylated substrate, pTCTP, by immunostaining eighty-eight neuroblastomas. Digitally scanned slides were scored using image analysis software. The median PLK1 and pTCTP proliferation indices (PIs) were 4.6 and 1% respectively. There was moderate positive correlation between PLK1 and pTCTP (ρ = 0.65). The PIs for both markers were significantly higher in neuroblastomas from patients with adverse clinical (advanced-stage, high-risk group, primary abdominal compared to extra-abdominal sites), biological (MYCN amplification, 1p deletion, 17q gain) and pathological (undifferentiated or poorly differentiated status, high mitosis-karyorrhexis index, [MKI], unfavorable histology) factors. Using Cox regression models, higher-than-median PLK1 and pTCTP PIs were associated with a shorter overall survival (OS) and event-free survival (EFS) in the univariate analyses. In the multivariate analyses, a high PLK1 PI count was associated with significantly shorter OS and EFS, independent of MYCN amplification and MKI; in addition, the significantly shorter EFS was independent of the risk-group. After adjustment for MKI and MYCN amplification, and for risk-group, high pTCTP PI was also associated with significantly shorter OS. Our study shows that PLK1 provides valuable prognostic information in patients with neuroblastomas.
authors: School of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK. pramila.ramani@bristol.ac.uk.|Department of Histopathology, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Infirmary, Bristol, BS2 8HW, UK. pramila.ramani@bristol.ac.uk.
authors: Pramila
authors: P
authors: Ramani
authors: Clinical Trials and Evaluation Unit, University of Bristol, School of Clinical Sciences, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors: Rachel
authors: R
authors: Nash
authors: Department of Histopathology, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors: Emile
authors: E
authors: Sowa-Avugrah
authors: Clinical Trials and Evaluation Unit, University of Bristol, School of Clinical Sciences, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors: Chris
authors: C
authors: Rogers
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000090324:Tumor Protein, Translationally-Controlled 1; D055815:Young Adult; D000097869:Polo-Like Kinase 1
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090324:Tumor Protein, Translationally-Controlled 1; D000097869:Polo-Like Kinase 1; C459801:MYCN protein, human; C000715647:TPT1 protein, human
keywords: Digital image analysis; Neuroblastoma; PhosphoTCTP; Polo-like kinase 1; Proliferation indices