Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas

被引:201
作者
Schiffman, Joshua D. [4 ,5 ]
Hodgson, J. Graeme [1 ]
VandenBerg, Scott R. [6 ]
Flaherty, Patrick [7 ,8 ]
Polley, Mei-Yin C. [1 ]
Yu, Mamie [1 ]
Fisher, Paul G. [9 ]
Rowitch, David H. [1 ,2 ,3 ]
Ford, James M. [10 ]
Berger, Mitchel S. [1 ]
Ji, Hanlee [10 ]
Gutmann, David H. [11 ]
James, C. David [1 ]
机构
[1] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Pediat, San Francisco, CA 94143 USA
[3] Eli & Edythe Broad Inst Regenerat Med & Stem Cell, San Francisco, CA USA
[4] Univ Utah, Div Pediat Hematol Oncol, Salt Lake City, UT USA
[5] Univ Utah, Dept Oncol Sci, Salt Lake City, UT USA
[6] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
[7] Stanford Univ, Dept Biochem, Palo Alto, CA 94304 USA
[8] Stanford Univ, Canc Biol Program, Palo Alto, CA 94304 USA
[9] Stanford Univ, Dept Neurol, Palo Alto, CA 94304 USA
[10] Stanford Univ, Dept Med Oncol, Palo Alto, CA 94304 USA
[11] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
关键词
IDH2; MUTATIONS; DUPLICATION; PATHWAY; ACTIVATION; FREQUENCY; CHILDHOOD; GLIOMAS; 7Q34; AGE;
D O I
10.1158/0008-5472.CAN-09-1851
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAF(V600E) 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. Cancer Res; 70(2); 512-9. (C)2010 AACR.
引用
收藏
页码:512 / 519
页数:8
相关论文
共 20 条
[1]   Analysis of the IDH1 codon 132 mutation in brain tumors [J].
Balss, Joerg ;
Meyer, Jochen ;
Mueller, Wolf ;
Korshunov, Andrey ;
Hartmann, Christian ;
von Deimling, Andreas .
ACTA NEUROPATHOLOGICA, 2008, 116 (06) :597-602
[2]   Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma [J].
Bar, Eli E. ;
Lin, Alex ;
Tihan, Tarik ;
Burger, Peter C. ;
Eberhart, Charles G. .
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2008, 67 (09) :878-887
[3]   Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].
Chin, L. ;
Meyerson, M. ;
Aldape, K. ;
Bigner, D. ;
Mikkelsen, T. ;
VandenBerg, S. ;
Kahn, A. ;
Penny, R. ;
Ferguson, M. L. ;
Gerhard, D. S. ;
Getz, G. ;
Brennan, C. ;
Taylor, B. S. ;
Winckler, W. ;
Park, P. ;
Ladanyi, M. ;
Hoadley, K. A. ;
Verhaak, R. G. W. ;
Hayes, D. N. ;
Spellman, Paul T. ;
Absher, D. ;
Weir, B. A. ;
Ding, L. ;
Wheeler, D. ;
Lawrence, M. S. ;
Cibulskis, K. ;
Mardis, E. ;
Zhang, Jinghui ;
Wilson, R. K. ;
Donehower, L. ;
Wheeler, D. A. ;
Purdom, E. ;
Wallis, J. ;
Laird, P. W. ;
Herman, J. G. ;
Schuebel, K. E. ;
Weisenberger, D. J. ;
Baylin, S. B. ;
Schultz, N. ;
Yao, Jun ;
Wiedemeyer, R. ;
Weinstein, J. ;
Sander, C. ;
Gibbs, R. A. ;
Gray, J. ;
Kucherlapati, R. ;
Lander, E. S. ;
Myers, R. M. ;
Perou, C. M. ;
McLendon, Roger .
NATURE, 2008, 455 (7216) :1061-1068
[4]   Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas [J].
Forshew, Tim ;
Tatevosslan, Ruth G. ;
Lawson, Andrew R. J. ;
Ma, Jing ;
Neale, Geoff ;
Ogunkolade, Babatunji W. ;
Jones, Tania A. ;
Aarum, Johan ;
Dalton, James ;
Bailey, Simon ;
Chaplin, Tracy ;
Carter, Rowena L. ;
Gajjar, Amar ;
Broniscer, Alberto ;
Young, Bryan D. ;
Ellison, David W. ;
Sheer, Denise .
JOURNAL OF PATHOLOGY, 2009, 218 (02) :172-181
[5]   Genetic alterations in signaling pathways in melanoma [J].
Haluska, FG ;
Tsao, H ;
Wu, H ;
Haluska, FS ;
Lazar, A ;
Goel, V .
CLINICAL CANCER RESEARCH, 2006, 12 (07) :2301S-2307S
[6]   Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas [J].
Hartmann, Christian ;
Meyer, Jochen ;
Balss, Joerg ;
Capper, David ;
Mueller, Wolf ;
Christians, Arne ;
Felsberg, Joerg ;
Wolter, Marietta ;
Mawrin, Christian ;
Wick, Wolfgang ;
Weller, Michael ;
Herold-Mende, Christel ;
Unterberg, Andreas ;
Jeuken, Judith W. M. ;
Wesseling, Peter ;
Reifenberger, Guido ;
von Deimling, Andreas .
ACTA NEUROPATHOLOGICA, 2009, 118 (04) :469-474
[7]   Tandem Duplication Producing a Novel Oncogenic BRAF Fusion Gene Defines the Majority of Pilocytic Astrocytomas [J].
Jones, David T. W. ;
Kocialkowski, Sylvia ;
Liu, Lu ;
Pearson, Danita M. ;
Backlund, L. Magnus ;
Ichimura, Koichi ;
Collins, V. Peter .
CANCER RESEARCH, 2008, 68 (21) :8673-8677
[8]   KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab [J].
Lievre, Astrid ;
Bachet, Jean-Baptiste ;
Boige, Valerie ;
Cayre, Anne ;
Le Corre, Delphine ;
Buc, Emmanuel ;
Ychou, Marc ;
Bouche, Olivier ;
Landi, Bruno ;
Louvet, Christophe ;
Andre, Thierry ;
Bibeau, Frederic ;
Diebold, Marie-Daniele ;
Rougier, Philippe ;
Ducreux, Michel ;
Tomasic, Gorana ;
Emile, Jean-Francois ;
Penault-Llorca, Frederique ;
Laurent-Puig, Pierre .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (03) :374-379
[9]   Targeting the RAF-MEK-ERK pathway in cancer therapy [J].
Montagut, Clara ;
Settleman, Jeff .
CANCER LETTERS, 2009, 283 (02) :125-134
[10]   An integrated genomic analysis of human glioblastoma Multiforme [J].
Parsons, D. Williams ;
Jones, Sian ;
Zhang, Xiaosong ;
Lin, Jimmy Cheng-Ho ;
Leary, Rebecca J. ;
Angenendt, Philipp ;
Mankoo, Parminder ;
Carter, Hannah ;
Siu, I-Mei ;
Gallia, Gary L. ;
Olivi, Alessandro ;
McLendon, Roger ;
Rasheed, B. Ahmed ;
Keir, Stephen ;
Nikolskaya, Tatiana ;
Nikolsky, Yuri ;
Busam, Dana A. ;
Tekleab, Hanna ;
Diaz, Luis A., Jr. ;
Hartigan, James ;
Smith, Doug R. ;
Strausberg, Robert L. ;
Marie, Suely Kazue Nagahashi ;
Shinjo, Sueli Mieko Oba ;
Yan, Hai ;
Riggins, Gregory J. ;
Bigner, Darell D. ;
Karchin, Rachel ;
Papadopoulos, Nick ;
Parmigiani, Giovanni ;
Vogelstein, Bert ;
Velculescu, Victor E. ;
Kinzler, Kenneth W. .
SCIENCE, 2008, 321 (5897) :1807-1812