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Genomic amplification of orthodenticle homologue 2 in
medulloblastomas
Boon K, Eberhart CG, Riggins GJ
Departments of Neurosurgery and Pathology, Johns Hopkins University School
of Medicine, Baltimore, Maryland.
To better understand the genetic basis of medulloblastoma development, we
sought genomic amplifications and deletions in these tumors using digital
karyotyping in combination with expression analysis.
Five medulloblastoma
genomes were karyotyped by sequencing an average of 195,745 genomic DNA tags
for each analysis.
Tags were tallied at unique positions and mapped to the
human genome to determine DNA copy numbers in high resolution along each
chromosome.
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.
The three genes and a predicted open reading frame flanking
OTX2 in the 14q amplicon were not amplified in at least one of the other
nine amplicons, implicating OTX2 as the gene target conferring a selective
advantage.
The degree of OTX2 amplification ranged from 8 copies to over 50
copies of the gene.
OTX2 transcript was highly and specifically expressed in
medulloblastoma or developing cells.
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.
PMID: 15705863 [PubMed - in process]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15705863
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