Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma.
Relatively little is known about the molecular changes that promote the formation or growth of pilocytic astrocytomas. We investigated genomic alterations in 25 pilocytic astrocytomas, including 5 supratentorial and 20 posterior fossa tumors, using oligonucleotide array comparative genomic hybridization. Large changes were identified in 7 tumors and included gains of chromosomes 5, 6, and 7 and losses of chromosomes 16, 17, 19, and 22. The most common alteration was a 1.9-MB region of low-level gain at chromosome 7q34 identified in 17 of 20 posterior fossa tumors. In most tumors, the region of gain ended within the BRAF locus and encompassed only exons that encode the BRAF kinase domain. We confirmed copy number increase at the 7q34 locus using quantitative polymerase chain reaction with primers adjacent to the HIPK2, RAB19B, and BRAF genes. Western blot analysis revealed that 3 of 6 pilocytic astrocytomas with 7q34 gain contained high levels of phosphorylated extracellular signal-related kinase (ERK) and nitrogen-activated protein kinase/ERK kinase (MEK), while 1 tumor lacking 7q34 gain and 2 normal brain specimens did not. Immunohistochemical stains of a tissue microarray containing 43 pilocytic astrocytoma identified ERK phosphorylation in 35 (81%). These data indicate that focal gains at chromosome 7q34 and increased BRAF-MEK-ERK signaling are common findings in sporadic pilocytic astrocytomas.
Bar
Eli E
EE
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ebar1@jhmi.edu
Lin
Alex
A
Tihan
Tarik
T
Burger
Peter C
PC
Eberhart
Charles G
CG
D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases