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

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.

1p36 Tumor Suppression—A Matter of Dosage?

“…In neuroblastomas, low CHD5 expression is associated with high-risk features such as 1p deletion, amplified MYCN oncogene, and advanced stage (41). Furthermore, low CHD5 mRNA and protein expression in neuroblastomas are significantly associated with poor patient outcome, even when adjusted for established prognostic variables (32,42). Together, this suggests that CHD5 is a neuronal gene whose dose reduction contributes to tumor development by inhibiting the p14…”

The Tumor Suppressor Chromodomain Helicase DNA-binding Protein 5 (CHD5) Remodels Nucleosomes by Unwrapping

“…tion of 1p36.3 and promoter silencing is correlated with a poor prognosis, and neuroblastoma cells that express CHD5 are more responsive to treatment than those that have lost CHD5 expression (9).…”

899 A Three-gene Expression Signature Model for Risk Stratification of Patients With Neuroblastoma

“…CHD5 is a tumor suppressor gene located on chromosome 1p36.31, region recurrently lost in high-risk neuroblastoma (17)(18)(19)(20)(21). Expression of this ATPdependent chromatin remodeling helicase has been found to be restricted to neuronalderived tissues and absent in neuroblastoma cell lines and neuroblastoma primary tumors with high-risk features, undifferentiated neuroblasts, MYCN amplification, advanced stage, and 1p monosomy (18,21).…”