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Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Lookup NU author(s): Dr Stephen Crosier, Professor Simon BaileyORCiD

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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.

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Author(s): Clarke M, Mackay A, Ismer B, Pickles JC, Tatevossian RG, Newman S, Bale TA, Stoler I, Izquierdo E, Temelso S, Carvalho DM, Molinari V, Burford A, Howell L, Virasami A, Fairchild AR, Avery A, Chalker J, Kristiansen M, Haupfear K, Dalton JD, Orisme W, Wen J, Hubank M, Kurian KM, Rowe C, Maybury M, Crosier S, Knipstein J, Schüller U, Kordes U, Kram DE, Snuderl M, Bridges L, Martin AJ, Doey LJ, Al-Sarraj S, Chandler C, Zebian B, Cairns C, Natrajan R, Boult JKR, Robinson SP, Sill M, Dunkel IJ, Gilheeney SW, Rosenblum MK, Hughes D, Proszek PZ, Macdonald TJ, Preusser M, Haberler C, Slavc I, Packer R, Ng HK, Caspi S, Popović M, Faganel Kotnik B, Wood MD, Baird L, Davare MA, Solomon DA, Olsen TK, Brandal P, Farrell M, Cryan JB, Capra M, Karremann M, Schittenhelm J, Schuhmann MU, Ebinger M, Dinjens WNM, Kerl K, Hettmer S, Pietsch T, Andreiuolo F, Driever PH, Korshunov A, Hiddingh L, Worst BC, Sturm D, Zuckermann M, Witt O, Bloom T, Mitchell C, Miele E, Colafati GS, Diomedi-Camassei F, Bailey S, Moore AS, Hassall TEG, Lowis SP, Tsoli M, Cowley MJ, Ziegler DS, Karajannis MA, Aquilina K, Hargrave DR, Carceller F, Marshall LV, Von Deimling A, Kramm CM, Pfister SM, Sahm F, Baker SJ, Mastronuzzi A, Carai A, Vinci M, Capper D, Popov S, Ellison DW, Jacques TS, Jones DTW, Jones C

Publication type: Article

Publication status: Published

Journal: Cancer Discovery

Year: 2020

Volume: 10

Issue: 7

Pages: 942-963

Print publication date: 01/07/2020

Online publication date: 01/04/2020

Acceptance date: 20/03/2020

ISSN (print): 2159-8274

ISSN (electronic): 2159-8290

Publisher: AACR Journals

URL: https://doi.org/10.1158/2159-8290.CD-19-1030

DOI: 10.1158/2159-8290.CD-19-1030

PubMed id: 32238360

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