Nucleolin expression has prognostic value in neuroblastoma patients

Summary

Background

Neuroblastoma (NB) represents the most frequent form of extra-cranial solid tumour of infants, responsible for 15% of childhood cancer deaths. Nucleolin (NCL) prognostic value in NB was investigated.

Methods

NCL protein expression was retrospectively evaluated in tumour samples of NB patients at diagnosis and after chemotherapy. NCL prognostic value at mRNA level was assessed in a cohort of 20 patients with stage 4 NB (qPCR20, n=20, discovery dataset) and in the MultiPlatform786 including 786 patients of all stages (validation dataset). Overall and event-free survival curves were plotted by Kaplan-Meier method and compared by log-rank test.

Findings

NCL protein, down-modulated after chemotherapy in association with features of neuroblastic differentiation,resulted statistically significantly overexpressed in NB tumours and higher in stage 4 compared to stage 1,2,3 patients. In the stage 4 patients cohort qPCR20, patients with high NCLmRNA expression revealed a statisticallysignificant lower survival probability than those with low NCL expression (OS: HR 4.1 95%CI 1.2–13.8; p=0.0215[Log-rank test], EFS: HR 4.1 95%CI 1.2–14.0, p=0.0197[Log-rank test]). In the MultiPlatform786 ( n=786), multivariate analysis suggested that NCL expression has a statistically significant prognostic value even in the model adjusted for established prognostic markers. NCL expression significantly stratified also patients with >18 months and stage 4 tumour(OS: HR 1.8 95%CI 1.2–2.7, p=0.0009[Log-rank test]; EFS: HR 1.7 95%CI 1.1–2.5, p=0.002[Log-rank test]), patients with>18 months stage 4 with MYCN non amplified tumour[EFS: HR 2.3 95%CI 1.2–4.7, p=0.01[Log-rank test]), and patients with MYCN non amplified and MYC high [OS: HR 11.9 95%CI 2.3–62.4, p=0.003[Log-rank test]; EFS: HR 7.2 95%CI 1.6–33.4, p=0.01[Log-rank test]) . A statistically significant correlation between NCL and MYCN, MYC, and TERT was found in independent datasets (MultiPlatform786 ( n=786) and Agilent394 ( n=394). Gene set enrichment analysis revealed a statisticallysignificant positive enrichment of MYC target genes and genes involved in telomerase maintenance.

Interpretation

NCL is a novel and independent (adjusting for age, INSS stage, and MYCN status) prognostic marker for NB.

Funding

IMH-EuroNanoMed II-2015 and AIRC-IG.