Abstract
Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Akhavan D, Pourzia AL, Nourian AA, Williams KJ, Nathanson D, Babic I et al (2013) De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. Cancer Discov 3:534–547
Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA et al (2013) EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 12:220–229
Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD et al (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369
Benbir G, Sayilir I, Oz B et al (2008) Bilateral thalamic glioma. A case report. J Neurol Sci 25:301–305
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477
Broniscer A, Hwang SN, Chamdine O, Lin T, Pounds S, Onar-Thomas A et al (2018) Bithalamic gliomas may be molecularly distinct from their unilateral high-grade counterparts. Brain Pathol 28:112–120
Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH et al (2008) Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 26:5603–5609
Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cancer Genome Atlas Research Network et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498
Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474
Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA et al (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164:550–563
Di Rocco C, Iannelli A (2002) Bilateral thalamic tumors in children. Childs Nerv Syst 18:440–444
Fortin JP, Labbe A, Lemire M, Zanke BW, Hudson TJ, Fertig EJ et al (2014) Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biol 15:503
Gudowius S, Engelbrecht V, Messing-Junger M, Reifenberger G, Gartner J (2002) Diagnostic difficulties in childhood bilateral thalamic astrocytomas. Neuropediatrics 33:331–335
Hirano T, Yasuda H, Tani T, Hamamoto J, Oashi A, Ishioka K et al (2015) In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget 6:38789–38803
Jain P, Mohamed A, Sigamani E, Suri V, Mahapatra AK, Kumar A et al (2013) Bilateral thalamic lesions in a child. Eur Neurol 70:33–34
Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM et al (2006) Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3:e485
Kline CN, Joseph NM, Grenert JP, van Ziffle J, Talevich E, Onodera C et al (2017) Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro Oncol 19:699–709
Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR et al (2017) Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32:520–537
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024
Messing-Junger AM, Floeth FW, Pauleit D, Reifenberger G, Willing R, Gartner J et al (2002) Multimodal target point assessment for stereotactic biopsy in children with diffuse bithalamic astrocytomas. Childs Nerv Syst 18:445–449
Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G et al (2014) Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343:72–76
Niu X, Wang T, Yang Y, Gan Y, Li J, Liu Y et al (2018) Prognostic factors for the survival outcome of bilateral thalamic glioma: an integrated survival analysis. World Neurosurg 110:e222–e230
Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS (2018) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol 20:iv1–iv86
Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M et al (2013) Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 8:179–184
Pandey N, Singh PK, Mahapatra AK, Kakkar A, Sharma BS (2014) Pediatric bilateral large concurrent thalamic glioblastoma: an unusual case report. J Pediatr Neurosci 9:76–78
Park JY, Cohen C, Lopez D, Ramos E, Wagenfuehr J, Rakheja D (2016) EGFR Exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol 40:1713–1718
Peereboom DM, Shepard DR, Ahluwalia MS, Brewer CJ, Agarwal N, Stevens GH et al (2010) Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol 98:93–99
Peruzzi L, Iuvone L, Ruggiero A, Colosimo C, Stefanini MC, Riccardi R (2016) Neuropsychological deterioration predicts tumor progression in a young boy with bithalamic glioma. Appl Neuropsychol Child 5:76–81
Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H et al (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584
Rafique MZ, Ahmad MN, Yaqoob N, Ahsan H (2007) Diffuse bilateral thalamic astrocytoma. J Coll Phys Surg Pak 17:170–172
Rajput DK, Mehrotra A, Srivastav AK, Kumar R, Mahapatra AK (2010) Bilateral thalamic glioma in a 6-year-old child. J Pediatr Neurosci 5:45–48
Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S et al (2018) Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med 24:638–646
Ruan Z, Kannan N (2018) Altered conformational landscape and dimerization dependency underpins the activation of EGFR by αC-β4 loop insertion mutations. Proc Natl Acad Sci USA 115:e8162–e8171
Sarkaria JN, Yang L, Grogan PT, Kitange GJ, Carlson BL, Schroeder MA et al (2007) Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel. Mol Cancer Ther 6:1167–1174
Sharaf AF, Hamouda ES, Teo JG (2016) Bilateral thalamic and right fronto-temporo-parietal gliomas in a 4 years old child diagnosed by magnetic resonance imaging. J Radiol Case Rep 10:1–13
Solomon DA, Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJ et al (2016) Diffuse midline gliomas with histone H3–K27M mutation: A series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 26:569–580
Sonoda Y, Ozawa T, Hirose Y, Aldape KD, McMahon M, Berger MS et al (2001) Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res 61:4956–4960
Steinbok P, Gopalakrishnan CV, Hengel AR, Vitali AM, Poskitt K, Hawkins C et al (2016) Pediatric thalamic tumors in the MRI era: a Canadian perspective. Childs Nerv Syst 32:269–280
Triche TJ, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD (2013) Low-level processing of Illumina Infinium DNA Methylation BeadArrays. Nucleic Acids Res 41:e90
Vivanco I, Robins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL et al (2012) Differential sensitivity of glioma-versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2:458–471
Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS et al (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969
Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253
Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450
Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL et al (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177
Yoshida M, Fushiki S, Takeuchi Y, Takanashi M, Imamura T, Shikata T et al (1998) Diffuse bilateral thalamic astrocytomas as examined serially by MRI. Childs Nerv Syst 14:384–388
Acknowledgements
We thank the staff of the UCSF Clinical Cancer Genomics Laboratory for assistance with genetic profiling. B.A. Orr is supported by the National Cancer Institute, National Institutes of Health (P30 CA021765) and the American Lebanese Syrian Associated Charities (ALSAC). D.A. Solomon is supported by the NIH Director’s Early Independence Award from the Office of the Director, National Institutes of Health (DP5 OD021403) and a Developmental Research Program Award from the UCSF Brain Tumor SPORE grant from the National Cancer Institute, National Institutes of Health (P50 CA097257).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
S.J. Allen is a current employee of Illumina, Inc. No potential conflicts of interest were disclosed by any of the other authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mondal, G., Lee, J.C., Ravindranathan, A. et al. Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta Neuropathol 139, 1071–1088 (2020). https://doi.org/10.1007/s00401-020-02155-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-020-02155-5