1. Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes
- Author
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Michael Karremann, Olaf Witt, Tabitha Bloom, Winand N.M. Dinjens, Felipe Andreiuolo, Michael Farrell, Scott Newman, Simone Hettmer, James Dalton, Leslie R. Bridges, Jens Schittenhelm, Martin Ebinger, Thomas S. Jacques, Francesca Diomedi-Camassei, Dominik Sturm, Jane Chalker, Matija Snuderl, David W. Ellison, Paula Proszek, Irene Slavc, Matthias A. Karajannis, Giovanna Stefania Colafati, Louise Howell, Christine Haberler, Simon Bailey, Barbara C. Worst, David A. Solomon, Andrew J. Martin, Stefan M. Pfister, Maria Vinci, Ho Keung Ng, Kelly Haupfear, Mellissa Maybury, Stephen Gilheeney, Bassel Zebian, Martin Sill, David T.W. Jones, Pablo Hernáiz Driever, Martin U. Schuhmann, Angela Mastronuzzi, Jessica K.R. Boult, Matthew Clarke, Rachael Natrajan, Kornelius Kerl, Lawrence Doey, Alex Virasami, Andrey Korshunov, Christof M. Kramm, Jane Cryan, David E. Kram, Timothy E.G. Hassall, Debbie Hughes, Claire Mitchell, Chris Jones, Monika A. Davare, Evelina Miele, Safa Al-Sarraj, Sara Temelso, Catherine Rowe, Suzanne J. Baker, Sergey Popov, Torsten Pietsch, Matthew D. Wood, Roger J. Packer, Lynley V. Marshall, Michael Capra, Valeria Molinari, Diana Carvalho, Marc Zuckermann, Andreas von Deimling, Uwe Kordes, Kathreena M Kurian, Shani Caspi, Ira J. Dunkel, Wilda Orisme, Ulrich Schüller, Claire Cairns, Matthias Preusser, Kristian Aquilina, Petter Brandal, Stephen Lowis, Iris Stoler, Christopher Chandler, Lissa C. Baird, Marc K. Rosenblum, Ji Wen, Felix Sahm, Barbara Faganel Kotnik, Stephen Crosier, Mara Popović, Andrea Carai, Lotte Hiddingh, Thale Kristin Olsen, Fernando Carceller, Simon P. Robinson, Maria Tsoli, Ruth G. Tatevossian, Anna Burford, Mike Hubank, Elisa Izquierdo, Tejus Bale, David Capper, Andrew S. Moore, David S. Ziegler, Amy R Fairchild, Aimee Avery, Alan Mackay, Jessica C Pickles, Mark Kristiansen, Jeffrey Knipstein, Darren Hargrave, Mark J. Cowley, Tobey J. MacDonald, Britta Ismer, and Pathology
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0301 basic medicine ,Oncology ,Disease specific ,medicine.medical_specialty ,Population ,Genome ,Article ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Proto-Oncogene Proteins ,Internal medicine ,ROS1 ,medicine ,Humans ,education ,Grading (tumors) ,Gene ,Exome sequencing ,education.field_of_study ,business.industry ,Receptor Protein-Tyrosine Kinases ,Infant ,Glioma ,Protein-Tyrosine Kinases ,Prognosis ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Gene Fusion ,Neoplasm Grading ,business - Abstract
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890
- Published
- 2020