Dataset Information

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.

ABSTRACT: Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.

SUBMITTER: Jones DT

PROVIDER: S-EPMC3951336 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.

Jones David T W DT Hutter Barbara B Jäger Natalie N Korshunov Andrey A Kool Marcel M Warnatz Hans-Jörg HJ Zichner Thomas T Lambert Sally R SR Ryzhova Marina M Quang Dong Anh Khuong DA Fontebasso Adam M AM Stütz Adrian M AM Hutter Sonja S Zuckermann Marc M Sturm Dominik D Gronych Jan J Lasitschka Bärbel B Schmidt Sabine S Seker-Cin Huriye H Witt Hendrik H Sultan Marc M Ralser Meryem M Northcott Paul A PA Hovestadt Volker V Bender Sebastian S Pfaff Elke E Stark Sebastian S Faury Damien D Schwartzentruber Jeremy J Majewski Jacek J Weber Ursula D UD Zapatka Marc M Raeder Benjamin B Schlesner Matthias M Worth Catherine L CL Bartholomae Cynthia C CC von Kalle Christof C Imbusch Charles D CD Radomski Sylwester S Lawerenz Chris C van Sluis Peter P Koster Jan J Volckmann Richard R Versteeg Rogier R Lehrach Hans H Monoranu Camelia C Winkler Beate B Unterberg Andreas A Herold-Mende Christel C Milde Till T Kulozik Andreas E AE Ebinger Martin M Schuhmann Martin U MU Cho Yoon-Jae YJ Pomeroy Scott L SL von Deimling Andreas A Witt Olaf O Taylor Michael D MD Wolf Stephan S Karajannis Matthias A MA Eberhart Charles G CG Scheurlen Wolfram W Hasselblatt Martin M Ligon Keith L KL Kieran Mark W MW Korbel Jan O JO Yaspo Marie-Laure ML Brors Benedikt B Felsberg Jörg J Reifenberger Guido G Collins V Peter VP Jabado Nada N Eils Roland R Lichter Peter P Pfister Stefan M SM

Nature genetics 20130630 8

Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium ( ...[more]

PMID: 23817572

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Project description:Pilocytic astrocytomas occur rarely in adults and show aggressive tumor behavior. However, their underlying molecular-genetic events are largely uncharacterized. Hence, 59 adult pilocytic astrocytoma (APA) cases of classical histology were studied (MIB-1 LI: 1%-5%). Analysis of BRAF alterations using qRT-PCR, confirmed KIAA1549-BRAF fusion in 11 (19%) and BRAF-gain in 2 (3.4%) cases. BRAF-V600E mutation was noted in 1 (1.7%) case by sequencing. FGFR1-mutation and FGFR-TKD duplication were seen in 7/59 (11.9%) and 3/59 (5%) cases, respectively. Overall 36% of APAs harbored BRAF and/or FGFR genetic alterations. Notably, FGFR related genetic alterations were enriched in tumors of supratentorial region (8/25, 32%) as compared with other locations (P = 0.01). The difference in age of cases with FGFR1-mutation (Mean age ± SD: 37.2 ± 15 years) vs. KIAA1549-BRAF fusion (Mean age ± SD: 25.1 ± 4.1 years) was statistically significant (P = 0.03). Combined BRAF and FGFR alterations were identified in 3 (5%) cases. Notably, the cases with more than one genetic alteration were in higher age group (Mean age ± SD: 50 ± 12 years) as compared with cases with single genetic alteration (Mean age ± SD: 29 ± 10; P = 0.003). Immunopositivity of p-MAPK/p-MEK1 was found in all the cases examined. The pS6-immunoreactivity, a marker of mTOR activation was observed in 34/39 (87%) cases. Interestingly, cases with BRAF and/or FGFR related alteration showed significantly lower pS6-immunostatining (3/12; 25%) as compared with those with wild-type BRAF and/or FGFR (16/27; 59%) (P = 0.04). Further, analysis of seven IDH wild-type adult diffuse astrocytomas (DA) showed FGFR related genetic alterations in 43% cases. These and previous results suggest that APAs are genetically similar to IDH wild-type adult DAs. APAs harbor infrequent BRAF alterations but more frequent FGFR alterations as compared with pediatric cases. KIAA1549-BRAF fusion inversely correlates with increasing age whereas FGFR1-mutation associates with older age. Activation of MAPK/ERK/mTOR signaling appears to be an important oncogenic event in APAs and may be underlying event of aggressive tumor behavior. The findings provided a rationale for potential therapeutic advantage of targeting MAPK/ERK/mTOR pathway in APAs.

Dataset Information

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.

Publications

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.

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