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Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma

Abstract

Pilocytic astrocytoma, the most common childhood brain tumor1, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations2. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression3 and often becoming a chronic disease with substantial morbidities4. 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 gene5. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.

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Figure 1: New BRAF alterations in pilocytic astrocytoma.
Figure 2: NTRK2 is a new gene fusion target in pilocytic astrocytoma.
Figure 3: FGF pathway signaling molecules are recurrently altered in pilocytic astrocytoma.
Figure 4: Summary of MAPK pathway alterations in pilocytic astrocytoma.

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Acknowledgements

For technical support and expertise, we thank B. Haase, D. Pavlinic and B. Baying (EMBL Genomics Core Facility); M. Wahlers and R. Lück (EMBL High-Performance Computing Facility); the DKFZ Genomics and Proteomics Core Facility; M. Knopf (NCT Heidelberg); K. Schlangen, M. Metsger, K. Schulz, A. Nürnberger, A. Kovacsovics and M. Linser (Max Planck Institute for Molecular Genetics); S. Peetz-Dienhart and Y. Floer (University Hospital Münster); D.M. Pearson (University of Cambridge); and B. Huang, G. Zipprich, M. Heinold, R. Kabbe, A. Wittmann, L. Sieber and L. Linke (DKFZ). W. Stummer (Münster), B. Hoffmann (Münster), B. Rama (Osnabrück), H. Ebel (Hamm), H.A. Trost (Bayreuth) and U. Wildförster (Gelsenkirchen) provided detailed clinical information. We also thank GATC Biotech for sequencing services. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Additional support came from the German Cancer Research Center–Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the Max Planck Society, Genome Canada and the Canadian Institute for Health Research (CIHR) with cofunding from Genome BC, Génome Quebec, CIHR-ICR (Institute for Cancer Research) and C17 (N. Jabado), Ian's Friend Foundation (M.A.K.), the US National Institutes of Health (NIH; grants RO1CA105607 and P30HD018655 to S.L.P.), the Dutch Cancer Foundations KWF (2010-4713) and KIKA (M.K.), the Brain Tumour Charity (S.R.L. and V.P.C.) and the Pediatric Low-Grade Astrocytoma Foundation (M.W.K. and K.L.L.).

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D.T.W.J., S.R.L., D.A.K.Q., A.M.F., H.-J.W., A.M.S., S.H., M. Zuckermann, J.G., S. Schmidt, H.Ş.-C., H.W., S.B., E.P., S. Stark, B.R., D.F., C.C.B., C.v.K., P.v.S., R. Versteeg, M. Sultan, S.W., M.H. and J.F. performed and/or coordinated experimental work. B.H., N. Jäger, D.T.W.J., M.K., H.-J.W., T.Z., B.L., P.A.N., V.H., J.S., J.M., M. Zapatka, M. Schlesner, C.L.W., C.D.I., S.R., C.L., P.v.S., J.K., R. Volckmann and M. Ralser performed data analysis. A.K., M. Ryzhova, C.M., B.W., A.U., C.H.-M., T.M., A.E.K., M.E., M.U.S., Y.-J.C., S.L.P., A.v.D., O.W., M.H., M.A.K., C.G.E., W.S., K.L.L., M.W.K., V.P.C. and N. Jabado collected data and provided materials from study subject. D.T.W.J., B.H., N. Jäger, D.S., N. Jabado, R.E., P.L. and S.M.P. prepared the initial manuscript and figures. A.K., U.D.W., M.D.T., J.O.K., H.L., M.-L.Y., B.B., G.R., V.P.C., N. Jabado, R.E., P.L. and S.M.P. provided project leadership. All authors contributed to the final manuscript.

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Correspondence to Roland Eils or Peter Lichter or Stefan M Pfister.

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Supplementary information

Supplementary Figures

Supplementary Figures 1–7 (PDF 6288 kb)

Supplementary Table 1

Overview of the sample cohort, MAPK pathway alterations and sequencing statistics (XLSX 23 kb)

Supplementary Table 2

Somatic mutations detected in the pilocytic astrocytoma sequencing cohort (XLS 102 kb)

Supplementary Table 3

Summary of FGFR1 and related mutations in pilocytic astrocytoma and pediatric glioblastoma (XLSX 12 kb)

Supplementary Table 4

Summary of significantly mutated genes (XLSX 10 kb)

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Jones, D., Hutter, B., Jäger, N. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45, 927–932 (2013). https://doi.org/10.1038/ng.2682

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