title: High proliferation index, as determined by immunohistochemical expression of Aurora kinase B and geminin, indicates poor prognosis in neuroblastomas.
abstract: Expression profile analysis of cell cycle biomarkers provides a powerful index of the proliferative state of tumors, which is linked to disease aggressiveness. We investigated the impact of the biomarkers of S-G2-M phases of cell cycle, Aurora kinase B (AURKB) and geminin (GMNN), on disease progression in neuroblastomas. The expression of AURKB and GMNN was studied by immunostaining 84 neuroblastomas. A proliferation index (PI) was obtained on scanned immunostained slides using image analysis software. The median PI was 8.5 % for AURKB- and 16.8 % for GMNN-stained slides with a high correlation between the two (r s = 0.72, P < 0.001). The PI for both markers was significantly higher in neuroblastomas from patients with unfavorable clinical (high-risk group, advanced stage, age ≥18 months at presentation, 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, a higher-than-median AURKB and GMNN PI was associated with a significantly shorter overall survival (OS) and event-free survival (EFS) in univariable analysis. In multivariable analysis, a high AURKB PI was associated with significantly shorter OS and EFS, independent of MYCN amplification, and significantly shorter EFS, independent of MKI. High GMNN PI was also associated with significantly shorter OS and EFS after adjusting for MYCN amplification but failed to reach statistical significance after adjusting for MKI. Our study shows that in neuroblastomas, AURKB- or GMNN-based PI provides valuable prognostic information and high PI indicates aggressive disease.
authors.affiliation: School of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK, Pramila.Ramani@bristol.ac.uk.
authors.forename: Pramila
authors.initials: P
authors.lastname: Ramani
authors.forename: Emile
authors.initials: E
authors.lastname: Sowa-Avugrah
authors.forename: Margaret T
authors.initials: MT
authors.lastname: May
mesh_terms: D000293:Adolescent; D064107:Aurora Kinase B / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D005260:Female; D064248:Geminin / Q000032:analysis*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D008940:Mitotic Index / Q000379:methods*; D009447:Neuroblastoma / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; C577995:GMNN protein, human; D064248:Geminin; C576921:AURKB protein, human; D064107:Aurora Kinase B