For immunohistochemistry (IHC) staining, fully automated Immunostainer BenchMark® ULTRA Roche from Ventana Medical Systems was used. InterpretationĬollection and manipulation of human samples were approved by the competent Ethic Committee and informed consent was obtained from each patient in accordance with the Declaration of Helsinki. Gene set enrichment analysis revealed a statisticallysignificant positive enrichment of MYC target genes and genes involved in telomerase maintenance. A statistically significant correlation between NCL and MYCN, MYC, and TERT was found in independent datasets (MultiPlatform786 ( n=786) and Agilent394 ( n=394). 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 EFS: HR 1.7 95%CI 1.1–2.5, p=0.002), patients with>18 months stage 4 with MYCN non amplified tumour), and patients with MYCN non amplified and MYC high EFS: HR 7.2 95%CI 1.6–33.4, p=0.01). 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. 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, EFS: HR 4.1 95%CI 1.2–14.0, p=0.0197).
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.
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