Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Abstract

The tightly controlled network of cell cycle genes consists of a core of cyclin dependent kinases (CDKs) that are activated by periodically expressed cyclins. The activity of the cyclin-CDK complexes is regulated by cyclin dependent kinase inhibitors (CDKIs) and multiple signal transduction routes that converge on the cell cycle. Neuroblastoma are pediatric tumors that belong to the group of small round blue cell tumors, characterized by a fast proliferation. Here, we present high throughput analyses of cell cycle regulating genes in neuroblastoma. We analyzed a series of 82 neuroblastomas by comparative genomic hybridization arrays, single nucleotide polymorphism arrays, and Affymetrix expression arrays and analyzed the datasets in parallel with the R2 bioinformatic tool (http://r2.amc.nl). About 30% of the tumors had genomic amplifications, gains, or losses with shortest regions of overlap that suggested implication of a series of G1 cell cycle regulating genes. CCND1 (cyclin D1) and CDK4 were amplified or gained and the chromosomal regions containing the CDKN2 (INK4) group of CDKIs were frequently deleted. Cluster analysis showed that tumors with genomic aberrations in G1 regulating genes over-expressed E2F target genes, which regulate S and G2/M phase progression. These tumors have a poor prognosis. Our findings suggest that pharmacological inhibition of cell cycle genes might bear therapeutic promises for patients with high risk neuroblastoma.

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

“…Neuroblastoma has a complex genetic profile that can include MYCN amplification, somatic activating mutations in the ALK oncogene, and other aberrations that activate CDK4/6 activity (6,25). It has also recently been shown that high-risk neuroblastoma may be defined by activation of telomere maintenance mechanisms caused by MYCN amplification, TERT rearrangements, or ATRX mutations (26), and relapsed neuroblastomas are frequently associated with RAS/mitogen-activated protein kinase (MAPK) pathway mutations that could also influence ribociclib sensitivity (27).…”

“…CCND1, CDK4, and CDK6 have been shown to be highly expressed in neuroblastoma, and CCND1 and CDK6 expression were found to be uniformly high relative to other tumors (5)(6)(7). Genomic amplification of CCND1 (cyclin D1 tumors) and CDK4 and deletion of CDKN2A are correlated with poor prognosis and, notably, approximately 30% of neuroblastomas exhibit aberrations in genes which regulate the G 1 checkpoint (6). An RNAi kinome screen in neuroblastoma cell lines identified CDK4 as a potential therapeutic target (8).…”

Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe

“…Also, BIRC5 is established as an E2F target (Jiang et al 2004). In neuroblastoma, a high E2F activity is related to a bad prognosis (Molenaar et al 2011). …”

Histone deacetylase 10 promotes autophagy-mediated cell survival

“…The following probe sets were used to detect HDAC10 expression: neuroblastoma (AMC), 226672_s_at; neuroblastoma (NCI), 811025; and medulloblastoma (Heidelberg), A_23_P211673. Patient characteristics for the neuroblastoma (AMC), neuroblastoma (NCI), and medulloblastoma (Heidelberg) cohorts were previously published (31)(32)(33).…”

“…We reanalyzed publicly available expression data [Academic Medical Center (AMC) cohort; Gene Expression Omnibus (GEO) database accession no. GSE16476] from 40 advanced stage primary neuroblastomas (INSS stage 4) from patients before treatment with multimodal chemotherapy using the Web-based R2 microarray database (http://r2.amc.nl) (31) to determine HDAC1 to -11 expression levels. From all 11 classical HDACs, only HDAC10 expression significantly correlated with poor overall survival in this patient cohort (Table S1).…”