Abstract
Neuroblastoma, the most frequently occurring extracranial solid tumor of childhood, arises from neural crest-derived cells that are arrested at an early stage of differentiation in the developing sympathetic nervous system. There is an urgent need to identify clinically relevant biomarkers for better prognosis and treatment of this aggressive malignancy. Eyes Absent 1 (EYA1) is an essential transcriptional coactivator for neuronal developmental programs during organogenesis. Whether or not EYA1 is implicated in neuroblastoma and subcellular localization of EYA1 is relevant to clinical behaviour of neuroblastoma is not known. We studied EYA1 expression and subcellular localization by immunohistochemistry in tissue microarrays containing tumor specimens from 98 patients, 66 of which were characterized by known clinical prognostic markers of neuroblastoma. Immunostaining results were evaluated and statistically correlated with the degree of histologic differentiation and with neuroblastoma risk stratification group characteristics, including stage of disease, patient age, tumor histology and mitosis–karyorrhexis index (MKI), respectively. We found that EYA1 levels were significantly higher in neuroblastomas than in ganglioneuromas and ganglioneuroblastomas. EYA1 was more highly expressed in stage 1,2,3 or 4S tumors as compared to stage 4 tumors (P<0.01). Tumors with high levels of nuclear EYA1 were more frequently associated with high nuclear MYCN levels. These results suggest that modulation of expression and intracellular localization of EYA1 in neural crest cells may provide a novel direction for therapeutic strategies.
Highlights
Neuroblastoma, the most common extracranial tumor of childhood, accounts for 15% of childhood cancer deaths
Since Eyes Absent 1 (EYA1) has a known role in neurogenesis during development [18] and Eyes Absent (EYA) homologs, including EYA1, have recently been linked to other paediatric malignancies [7, 14], we investigated the expression of EYA1 in neuroblastoma
Relationship of relative EYA1 mRNA and protein levels to degree of histologic differentiation of neural crest tumors
Summary
Neuroblastoma, the most common extracranial tumor of childhood, accounts for 15% of childhood cancer deaths. Despite improvements in treatment during the past several decades, prognoses remain dire for patients with high-risk disease, which account for nearly half of children with neuroblastoma. A large proportion of these cases are associated with treatment-resistant tumors and frequent relapses, with a 5-year overall survival rate ranging from 20% to 50% [1]. The underlying oncogenic mechanisms of this aggressive malignancy are largely unknown. Aberrant expression of MYCN is strongly associated with poor outcome, making this oncoprotein one of few proposed targets in molecular therapy for neuroblastoma [1]. Novel molecular markers of tumor aggressiveness and targets for therapy are urgently needed to improve prognosis and treatment of this devastating disease
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