A Distinct Spectrum of Copy Number Aberrations in Pediatric High-Grade Gliomas

Abstract

Purpose: As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors.Experimental Design: We carried out copy number profiling by array comparative genomic hybridization using a 32K bacterial artificial chromosome platform on 63 formalin-fixed paraffin-embedded cases of high-grade glioma arising in children and young people (<23 years).Results: The genomic profiles of these tumors could be subclassified into four categories: those with stable genomes, which were associated with a better prognosis; those with aneuploid and those with highly rearranged genomes; and those with an amplifier genotype, which had a significantly worse clinical outcome. Independent of this was a clear segregation of cases with 1q gain (more common in children) from those with concurrent 7 gain/10q loss (a defining feature of adults). Detailed mapping of all the amplification and deletion events revealed numerous low-frequency amplifications, including IGF1R, PDGFRB, PIK3CA, CDK6, CCND1, and CCNE1, and novel homozygous deletions encompassing unknown genes, including those at 5q35, 10q25, and 22q13. Despite this, aberrations targeting the "core signaling pathways" in adult glioblastomas are significantly underrepresented in the pediatric setting.Conclusions: These data highlight that although there are overlaps in the genomic events driving gliomagenesis of all ages, the pediatric disease harbors a distinct spectrum of copy number aberrations compared with adults. Clin Cancer Res; 16(13); 3368-77. ©2010 AACR.

Targeting CDK6 in cancer: State of the art and new insights

“…[35][36][37] CDK6 is overexpressed in lymphoma, leukemia, glioma, glioblastoma, medulloblastoma, and cancers of squamous cells, salivary gland, bladder, pancreas and prostate. [38][39][40][41][42][43][44][45][46][47][48][49][50] In human prostate cancer cells, CDK6 has also been shown to bind androgen receptor and stimulate its activity in a kinase activity independent manner. 46 Blockage of CDK6 expression by microRNAs (miRNAs) has been shown to inhibit the proliferation of gliomas, medulloblastoma, prostate, bladder, gastric, hepatocellular, and lung cancer cells, indicating the significant role of CDK6 in the initiation and progression of these cancers.…”

Genetic Instability in Paediatric and Adult Brain Tumours

“…These studies have demonstrated that the retinoblastoma (RB), p53 and RTK/PI3K/MAPK pathways are commonly disrupted in adult and paediatric glioblastomas through various genetic mechanisms (TCGA, 2008;Parsons et al, 2008). Nevertheless, our data has demonstrated that paediatric tumours show deregulation of these core pathways by copy number alterations in less than half the frequency of that reported for adult tumours: 25% RTK/PI3K/MAPK, 19% p53 and 22% RB versus 59%, 70% and 66%, for adult glioblastoma (Figure 1) (Bax et al, 2010;TCGA, 2008). Even though isolated cases presented clear genomic events linked to activation of the sonic hedgehog (SHH) and Notch pathways activation, there is no evidence of consistently targeted pathways in paediatric high-grade gliomas.…”

“…The first studies using large-scale genome profiling techniques to identify the key genetic alterations of brain tumours were only recently published (Kool et al, 2008;Parsons et al, 2008 Thompson et al, 2006). Nevertheless, the number of such studies have been increasing on the past few years, with the first studies in paediatric glioma patients starting to emerge (Barrow et al, 2011;Bax et al, 2010;Paugh et al, 2010;Qu et al, 2010;Schiffman et al, 2010;Zarghooni et al, 2010).…”

“…The number of such studies specifically addressing childhood high-grade glioma has until recently been much lower. Nevertheless, several works specifically addressing these paediatric tumours, from ours and others groups, are beginning to emerge, providing increasing evidence that the paediatric high-grade glioma genome has certain key differences from that of histologically similar adult tumours (Barrow et al, 2011;Bax et al, 2010;Paugh et al, 2010;Qu et al, 2010;Rao et al, 2010;Schiffman et al, 2010;K.K. Wong et al, 2006;Zarghooni et al, 2010).…”

“…Even though isolated cases presented clear genomic events linked to activation of the sonic hedgehog (SHH) and Notch pathways activation, there is no evidence of consistently targeted pathways in paediatric high-grade gliomas. Nevertheless, low-frequency amplifications in childhood tumours included genes involved in cell cycle progression (CCND2, CDK4, MYC, and MYCN), receptor tyrosine kinases (RTKs) and ligands (EGFR, MET, IGF1R, PDGFB, and NRG1), members of the PI3K/MAPK pathway (PIK3C2B, PIK3C2G, PIK3R5, KRAS, AKT1, and S6K1), and p53 pathway regulation (MDM4) , s o m e o f t h e m k n o w n t o b e d e r e g u l a t e d a l s o i n a d u l t glioblastoma (Figure 2) (Bax et al, 2010;Paugh et al, 2010). In addition, homozygous deletions of tumour suppressor genes of known importance within the adult glioblastoma core signalling pathways included CDKN2C, PTEN, RB1, TP53, and TP73 (Figure 1) (TCGA, 2008;Parsons et al, 2008), albeit at considerably lower frequencies in paediatric versus adult tumours.…”