MYCN overexpression is linked to significant differences in nuclear DNA organization in neuroblastoma

Abstract

Neuroblastomas are the most common extracranial cancers in children. They have a complex morphology and heterogeneous clinical course. Amplification of the MYCN oncogene is seen in 50% of high-risk neuroblastomas and is associated with a poor clinical outcome with a higher rate of progression and relapse when compared with tumors without MYCN amplification. MYCN amplification drives genomic instability, dynamic remodeling of chromosomes and changes in nuclear organization. However, understanding of how the chromatin structure responds to MYC overexpression in neuroblastoma is nebulous. In the present study, we examined neuroblastoma samples with and without MYCN amplification as well as in the neuroblastoma cell line SH-EP transfected with MYCN pUHD. Our neuroblastoma cases segregated into one of three prognostic clusters of increasingly poor prognosis. Clusters I and II encompassed tumors with no MYCN amplification, while cluster III included tumors with MYCN amplification. Measurements of both the DNA structure (p<0.001) and structure of the DNA-free space (p < 0.001) showed significant DNA structural alterations associated with MYCN amplification indicating that there is a progressive disruption of nuclear DNA organization with MYCN amplification suggesting that MYCN may play an functional role in determining the nuclear structure in neuroblastoma.