Nucleolin expression has prognostic value in neuroblastoma patients
Davide Cangelosi,
Chiara Brignole,
Veronica Bensa,
Roberto Tamma,
Fabiana Malaguti,
Barbara Carlini,
Elena Giusto,
Enzo Calarco,
Patrizia Perri,
Domenico Ribatti,
Nuno André Fonseca,
Joao Nuno Moreira,
Alessandra Eva,
Loredana Amoroso,
Massimo Conte,
Alberto Garaventa,
Angela Rita Sementa,
Maria Valeria Corrias,
Mirco Ponzoni,
Fabio Pastorino
Affiliations
Davide Cangelosi
Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Genova, Italy
Chiara Brignole
Laboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, Genoa, Italy
Veronica Bensa
Laboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, Genoa, Italy
Roberto Tamma
Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy
Fabiana Malaguti
Department of Pathology, IRCCS IstitutoGianninaGaslini, Genoa, Italy
Barbara Carlini
Department of Pathology, IRCCS IstitutoGianninaGaslini, Genoa, Italy
Elena Giusto
Laboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, Genoa, Italy
Enzo Calarco
Laboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, Genoa, Italy
Patrizia Perri
Laboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, Genoa, Italy
Domenico Ribatti
Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy
Nuno André Fonseca
CNC – Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Coimbra, Portugal
Joao Nuno Moreira
CNC – Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Coimbra, Portugal; Univ Coimbra – University of Coimbra, CIBB, Faculty of Pharmacy, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, Portugal
Alessandra Eva
Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Genova, Italy
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 thatNCL 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.
