TY - JOUR
T1 - Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas
AU - Schiffman, Joshua D.
AU - Hodgson, J. Graeme
AU - Vandenberg, Scott R.
AU - Flaherty, Patrick
AU - Polley, Mei Yin C.
AU - Yu, Mamie
AU - Fisher, Paul G.
AU - Rowitch, David H.
AU - Ford, James M.
AU - Berger, Mitchel S.
AU - Ji, Hanlee
AU - Gutmann, David H.
AU - James, C. David
PY - 2010/1/15
Y1 - 2010/1/15
N2 - Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAFV600E) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAFV600E mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.
AB - Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAFV600E) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAFV600E mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.
UR - http://www.scopus.com/inward/record.url?scp=76549137130&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-1851
DO - 10.1158/0008-5472.CAN-09-1851
M3 - Article
C2 - 20068183
AN - SCOPUS:76549137130
SN - 0008-5472
VL - 70
SP - 512
EP - 519
JO - Cancer research
JF - Cancer research
IS - 2
ER -