A B S T R A C T PurposeTo define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). Patients and MethodsWe conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors. ResultsSignificant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFR␣ signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes. ConclusionIntegrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFR␣ may be a useful target for pediatric HGG, including diffuse pontine gliomas.

The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, complete cardiac regeneration has been demonstrated in fish and newborn mice following resection of the cardiac apex. However, it remained entirely unclear whether the mammalian heart can also completely regenerate following a complex cardiac ischemic injury. We established a protocol to induce a severe heart attack in one-day-old mice using left anterior descending artery (LAD) ligation. LAD ligation triggered substantial cardiac injury in the left ventricle defined by Caspase 3 activation and massive cell death. Ischemia-induced cardiomyocyte death was also visible on day 4 after LAD ligation. Remarkably, 7 days after the initial ischemic insult, we observed complete cardiac regeneration without any signs of tissue damage or scarring. This tissue regeneration translated into long-term normal heart functions as assessed by echocardiography. In contrast, LAD ligations in 7-day-old mice resulted in extensive scarring comparable to adult mice, indicating that the regenerative capacity for complete cardiac healing after heart attacks can be traced to the first week after birth. RNAseq analyses of hearts on day 1, day 3, and day 10 and comparing LAD-ligated and sham-operated mice surprisingly revealed a transcriptional programme of major changes in genes mediating mitosis and cell division between days 1, 3 and 10 postnatally and a very limited set of genes, including genes regulating cell cycle and extracellular matrix synthesis, being differentially regulated in the regenerating hearts. We present for the first time a mammalian model of complete cardiac regeneration following a severe ischemic cardiac injury. This novel model system provides the unique opportunity to uncover molecular and cellular pathways that can induce cardiac regeneration after ischemic injury, findings that one day could be translated to human heart attack patients.

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.