Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma

Idoia Garcia,Patricia Galván,Cinzia Lavarino,Carla Casala,Nai-Kong V Cheung,Eva Rodríguez,Mark W Kieran,Carmen De Torres,Mariona Suñol,José Ríos,Jaume Mora,Antonio R Perez-Atayde,Gemma Mayol,Rani E George,Timothy R Gershon

doi:10.1186/1476-4598-9-277

Abstract

BackgroundThe chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response.ResultsWe provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis <12 months, low clinical stage, and favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P < 0.001).Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival.ConclusionsThe neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.

Highlights

Neuroblastic tumors (NTs) are embryonal cancers arising from neural crest derived sympathetic nervous system precursors
CHD5 protein expression in normal neural tissues is restricted to neuronal cells In normal human neural tissue sections, CHD5 immunoreactivity was found restricted to neurons, whereas glial cells were consistently negative (Figure 1A, C, D and 1E)
No CHD5 protein expression was observed in Glial fibrillary acidic protein (GFAP) positive glial cells (Figure 1G and 1H)

Summary

Introduction

Neuroblastic tumors (NTs) are embryonal cancers arising from neural crest derived sympathetic nervous system precursors. These neoplasms are the most common extracranial solid tumors in childhood and account for approximately 15% of all pediatric oncology deaths [1]. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response

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