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.