Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas

Abstract

Overall, pediatric high-grade glioma (pHGG) has a poor prognosis, in part due to the lack of understanding of the underlying biology. High-resolution 244 K oligo array comparative genomic hybridization (CGH) was used to analyze DNA from 38 formalin-fixed paraffin-embedded predominantly pretreatment pHGG samples, including 13 diffuse intrinsic pontine gliomas (DIPGs). The patterns of gains and losses were distinct from those seen in HGG arising in adults. In particular, we found 1q gain in up to 27% of our cohort compared with 9% reported in adults. A total of 13% had a balanced genetic profile with no large-scale copy number alterations. Homozygous loss at 8p12 was seen in 6 of 38 (16%) cases of pHGG. This novel deletion, which includes the ADAM3A gene, was confirmed by quantitative real-time PCR (qPCR). Loss of CDKN2A/CDKN2B in 4 of 38 (10%) samples by oligo array CGH was confirmed by fluorescent in situ hybridization on tissue microarrays and was restricted to supratentorial tumors. Only ∼50% of supratentorial tumors were positive for CDKN2B expression by immunohistochemistry (IHC), while ∼75% of infratentorial tumors were positive for CDKN2B expression (P = 0.03). Amplification of the 4q11-13 region was detected in 8% of cases and included PDGFRA and KIT, and subsequent qPCR analysis was consistent with the amplification of PDGFRA. MYCN amplification was seen in 5% of samples being significantly associated with anaplastic astrocytomas (P= 0.03). Overall, DIPG shared similar spectrum of changes to supratentorial HGG with some notable differences, including high-frequency loss of 17p and 14q and lack of CDKN2A/CDKN2B deletion. Informative genetic data providing insight into the underlying biology and potential therapeutic possibilities can be generated from archival tissue and typically small biopsies from DIPG. Our findings highlight the importance of obtaining pretreatment samples.

SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status

“…The HZD located at 8p11.23-p11.22 and found in two MGUS patients is also of particular interest, as it contains only the ADAM3A gene, in which HZD has recently been reported in pediatric high-grade glioma and diffuse intrinsic pontine gliomas. 51,52 Other relevant genes, such as the tumor suppressor gene PTPRD, the transcriptional regulators ZNF709, ZNF564 and ZNF490, and UBE2N, which plays a role in the error-free DNA repair pathway, were included in the reported focal-recurrent CNA. 53,54 Fragile sites are gaps, constrictions or breaks in metaphase chromosomes that arise when cells are exposed to a perturbation of the DNA replication process.…”

Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma

“…[5][6][7][8] Because of limited sample sizes, it is less clear whether DIPGs show the same molecular signatures as nonbrainstem pediatric HGGs, or if they also show a distinct spectrum of alterations. In studies with focused analyses of specific genes in small cohorts, approximately half of DIPGs contained TP53 mutations, and three (19%) of 16 high-grade DIPGs contained EGFR amplification.…”

“…However, no other common focal alterations were consistently detected, likely because of the limited numbers of tumors evaluated in each study. 6,7,12 …”

A new era for children with diffuse intrinsic pontine glioma: hope for cure?

“…Importantly, studies show a clearly distinct genetic profile of pediatric highgrade glioma (HGG) including DIPG as compared with adult HGG [11]. Moreover, DIPG differs from pediatric HGG occurring elsewhere in the brain, since several chromosomal abnormalities appear more frequently in DIPG than in pediatric HGG, including gains of chromosomes 1q, 2p, 7p, 8q and 9q and losses in chromosomes 10q, 16q and 17p [10,[12][13][14][15] Editorial arising in the thalamus, suggesting a shared origin of a common precursor cell population [13].…”

“…Other amplified genes in DIPG are hepatocyte growth factor receptor (MET ), IGF receptor 1 (IGF1R), EGF receptors (EGFR, ERBB4 and EGFRv3), poly-ADP-ribose polymerase (PARP ), VEGFA and the associated downstream pathways including PI3K-Akt-phosphomammalian target of rapamycin (MTOR) and retinoblastoma-associated protein (RB) pathway [10,[12][13][14][15] . Puget et al performed comparative genomic hybridization and gene expression profiling on 23 biopsy samples and identified two subgroups; the first characterized by oligodendroglial features appearing largely driven by PDGFR and the second by mesenchymal and angiogenesis characteristics showing overexpression of numerous proangiogenic genes including VEGFA [13].…”