Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes
Authors: Clarke Matthew , Mackay Alan , Ismer Britta , Pickles Jessica C. , Tatevossian Ruth G. , Newman Scott , Bale Tejus A. , Stoler Iris , Izquierdo Elisa , Temelso Sara , Carvalho Diana M. , Molinari Valeria , Burford Anna , Howell Louise , Virasami Alex , Fairchild Amy R. , Avery Aimee , Chalker Jane , Kristiansen Mark , Haupfear Kelly , Dalton James D. , Orisme Wilda , Wen Ji , Hubank Michael , Kurian Kathreena M. , Rowe Catherine , Maybury Mellissa , Crosier Stephen , Knipstein Jeffrey , Schüller Ulrich , Kordes Uwe , Kram David E. , Snuderl Matija , Bridges Leslie , Martin Andrew J. , Doey Lawrence J. , Al-Sarraj Safa , Chandler Christopher , Zebian Bassel , Cairns Claire , Natrajan Rachael , Boult Jessica K.R. , Robinson Simon P. , Sill Martin , Dunkel Ira J. , Gilheeney Stephen W. , Rosenblum Marc K. , Hughes Debbie , Proszek Paula Z. , Macdonald Tobey J. , Preusser Matthias , Haberler Christine , Slavc Irene , Packer Roger , Ng Ho-Keung , Caspi Shani , Popović Mara , Faganel Kotnik Barbara , Wood Matthew D. , Baird Lissa , Davare Monika Ashok , Solomon David A. , Olsen Thale Kristin , Brandal Petter , Farrell Michael , Cryan Jane B. , Capra Michael , Karremann Michael , Schittenhelm Jens , Schuhmann Martin U. , Ebinger Martin , Dinjens Winand N.M. , Kerl Kornelius , Hettmer Simone , Pietsch Torsten , Andreiuolo Felipe , Driever Pablo Hernáiz , Korshunov Andrey , Hiddingh Lotte , Worst Barbara C. , Sturm Dominik , Zuckermann Marc , Witt Olaf , Bloom Tabitha , Mitchell Clare , Miele Evelina , Colafati Giovanna Stefania , Diomedi-Camassei Francesca , Bailey Simon , Moore Andrew S. , Hassall Timothy E.G. , Lowis Stephen P. , Tsoli Maria , Cowley Mark J. , Ziegler David S. , Karajannis Matthias A. , Aquilina Kristian , Hargrave Darren R. , Carceller Fernando , Marshall Lynley V. , von Deimling Andreas , Kramm Christof M. , Pfister Stefan M. , Sahm Felix , Baker Suzanne J. , Mastronuzzi Angela , Carai Andrea , Vinci Maria , Capper David , Popov Sergey , Ellison David W. , Jacques Thomas S. , Jones David T.W. , Jones Chris 
Published: April 2020

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