Which genes are thought to be involved in medulloblastoma development?
['Medulloblastomas, the most frequent malignant brain tumours affecting children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1, SUFU) are observed in many of these tumours, high throughput genomic analyses have identified few other recurring mutations', 'Mutagenesis significantly increased medulloblastoma frequency and identified 17 candidate cancer genes, including orthologs of genes somatically mutated (PTEN, CREBBP) or associated with poor outcome (PTEN, MYT1L) in the human disease. Strikingly, these candidate genes were enriched for transcription factors (p=2x10-5), the majority of which (6/7; Crebbp, Myt1L, Nfia, Nfib, Tead1 and Tgif2) were linked within a single regulatory network enriched for genes associated with a differentiated neuronal phenotype', 'Igf2, previously implicated in medulloblastoma, was the most differentially expressed gene in murine tumours with network perturbation', 'PCDH10 is a candidate tumour suppressor gene in medulloblastoma', 'The aim of this study was to investigate the genetic and epigenetic mechanisms contributing to PCDH10 down-regulation in medulloblastoma', 'We report a very focal homozygous deletion on chromosome 4q28.3 harbouring the PCDH10 gene. We demonstrate that PCDH10 transcription is down-regulated in 19/26 (73%) of medulloblastomas suggesting that other mechanisms also could be involved in gene repression', 'Our findings suggest that genetic and epigenetic deregulation of PCDH10 occurs in a significant portion of medulloblastoma patients. Failure to express PCDH10 may result in loss of inhibition of cell migration, thereby contributing to medulloblastoma progression', 'We found that the higher expression levels of BMI1 and PCGF2 genes were associated with significantly decreased patient survival', "Our analysis showed correlation between BMI1 and PCGF2 gene's expression and survival in children with medulloblastoma", 'Bmi1 is required for Hedgehog pathway-driven medulloblastoma expansion', 'These data provide the first demonstration that Bmi1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for Bmi1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate Bmi1 as a key factor required for Hh pathway-driven tumorigenesis', 'Genomic amplification of orthodenticle homologue 2 in medulloblastomas', 'Genomic alterations normally associated with medulloblastomas, including MYC amplification and isochromosome 17q, were easily detected. Surprisingly, analysis of only five genomes revealed novel amplicons on chromosome 14q, one of which contained the orthodenticle homologue 2 (OTX2) homeobox gene. DNA copy number analysis showed that OTX2 had undergone genomic amplification in 2 of 11 medulloblastoma cell lines and 8 of 42 primary tumors', 'Serial analysis of gene expression of 240 different human tumors or normal tissues revealed that 96% of all 783 OTX2 transcripts sequenced were in medulloblastomas or embryonic stem cells', 'OTX2 functions to specify the fate of neuroectoderm in various regions of the developing brain. This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene', 'Extensive hypermethylation of RASSF1A was detected frequently in medulloblastomas but not in the normal cerebellum (41/44 primary tumours versus 0/5 normal cerebella)', 'In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a consistent background of partial methylation in the normal cerebellum', 'These data therefore indicate that extensive methylation of RASSF1A, HIC1 and CASP8 are tumour-specific events in medulloblastoma', 'We conclude that epigenetic TSG inactivation is a significant feature of medulloblastoma, and identify RASSF1A, HIC1 and CASP8 as potentially critical genes in its pathogenesis', 'Biallelic epigenetic inactivation of the RASSF1A tumor suppressor gene in medulloblastoma development', 'Seventy-nine % (27 of 34) of primary tumors and 100% (8 of 8) of medulloblastoma cell lines displayed extensive tumor-specific DNA hypermethylation across the RASSF1A promoter-associated CpG island', "Hypermethylation was associated with epigenetic silencing of RASSF1A transcription in medulloblastoma cell lines, and RASSF1A expression in these lines was restored after treatment with the DNA-methyltransferase inhibitor 5-aza-2'-deoxycytidine", 'Epigenetic inactivation by biallelic hypermethylation therefore represents the primary mechanism of RASSF1A gene inactivation in medulloblastoma', 'RASSF1A hypermethylation is a frequent event in medulloblastoma tumorigenesis detectable in adult (5 of 7) and pediatric patients (22 of 27) and in all histological variants and age and sex groupings', 'Medulloblastoma, a brain tumor, develops in about 3% of NBCCS patients, and mutations in PTCH have also been described in a subset of sporadic medulloblastomas', 'Recently, a transgenic mouse hemizygous for the Ptch gene was generated by homologous recombination. Medulloblastomas were found in about 19% of these mice within the first 25 weeks after birth', 'We also examined the mRNA expression levels for the remaining Ptch allele, as well as for Gli1, a gene known to be transcriptionally activated by Ptch inactivation. Blot analysis of RNA from the 13 tumors shows that Ptch mRNA of appropriate size is expressed in all tumors at varying levels. Expression of Gli1 was increased in tumors compared to normal cerebellum. These results suggest that deletion of one copy of Ptch may be sufficient to promote medulloblastoma development in mice']
['Medulloblastomas are the most frequent malignant brain tumors affecting children. Disease development has been suggested to be associated with a significant number of genes, such as PTCH1, SUFU, PTEN, CREBBP, PTEN, MYT1L, NFIA, NFIB, TEAD1, TGIF2, IGF2, PCDH10, BMI1, MYC, OTX2, RASSF1A, HIC1, and CASP8.']
['PTCH1', 'SUFU', 'PTEN', 'CREBBP', 'PTEN', 'MYT1L', 'NFIA', 'NFIB', 'TEAD1', 'TGIF2', 'IGF2', 'PCDH10', 'BMI1', 'MYC', 'OTX2', 'RASSF1A', 'HIC1', 'CASP8']