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.
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.
Department of Oncogenomics, AMC, University of Amsterdam, Amsterdam, The Netherlands. j.j.molenaar@amc.uva.nl
Jan J
JJ
Molenaar
Jan
J
Koster
Marli E
ME
Ebus
Peter
P
van Sluis
Ellen M
EM
Westerhout
Katleen
K
de Preter
David
D
Gisselsson
Ingrid
I
Øra
Frank
F
Speleman
Huib N
HN
Caron
Rogier
R
Versteeg
D002869:Chromosome Aberrations; D016000:Cluster Analysis; D019938:Cyclin D1 / Q000235:genetics; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D050684:E2F Transcription Factors / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D018816:Genes, cdc; D006801:Humans; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050684:E2F Transcription Factors; D012333:RNA, Messenger; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases