Infant high grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes

TY - JOUR

T1 - Infant high grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes

AU - Clarke, Matthew

AU - Mackay, Alan

AU - Ismer, Britta

AU - Pickles, Jessica Chiara

AU - Tatevossian, Ruth G

AU - Newman, Scott

AU - Bale, Tejus A

AU - Stoler, Iris

AU - Izquierdo, Elisa

AU - Temelso, Sara

AU - Carvalho, Diana M

AU - Molinari, Valeria

AU - Burford, Anna

AU - Howell, Louise

AU - Virasami, Alex

AU - Fairchild, Amy R

AU - Avery, Aimee

AU - Chalker, Jane

AU - Kristiansen, Mark

AU - Haupfear, Kelly

AU - Dalton, James D

AU - Orisme, Wilda

AU - Wen, Ji

AU - Hubank, Michael

AU - Kurian, Kathreena M

AU - Rowe, Catherine

AU - Maybury, Mellissa

AU - Crosier, Stephen

AU - Knipstein, Jeffrey

AU - Schuller, Ulrich

AU - Kordes, Uwe

AU - Kram, David E

AU - Snuderl, Matija

AU - Bridges, Leslie

AU - Martin, Andrew J

AU - Doey, Lawrence J

AU - Al-Sarraj, Safa

AU - Chandler, Christopher

AU - Zebian, Bassel

AU - Cairns, Claire

AU - Natrajan, Rachael

AU - Boult, Jessica Kr

AU - Robinson, Simon P

AU - Sill, Martin

AU - Dunkel, Ira J

AU - Gilheeney, Stephen W

AU - Rosenblum, Marc K

AU - Hughes, Debbie

AU - Proszek, Paula Z

AU - MacDonald, Tobey J

AU - Preusser, Matthias

AU - Haberler, Christine

AU - Slavc, Irene

AU - Packer, Roger

AU - Ng, Ho-Keung

AU - Caspi, Shani

AU - Popovic, Mara

AU - Faganel Kotnik, Barbara

AU - Wood, Matthew D

AU - Baird, Lissa

AU - Davare, Monika Ashok

AU - Solomon, David A

AU - Olsen, Thale Kristin

AU - Brandal, Petter

AU - Farrell, Michael

AU - Cryan, Jane B

AU - Capra, Michael

AU - Karremann, Michael

AU - Schittenhelm, Jens

AU - Schuhmann, Martin U

AU - Ebinger, Martin

AU - Dinjens, Winand N M

AU - Kerl, Kornelius

AU - Hettmer, Simone

AU - Pietsch, Torsten

AU - Andreiuolo, Felipe

AU - Driever, Pablo Hernaiz

AU - Korshunov, Andrey

AU - Hiddingh, Lotte

AU - Worst, Barbara C

AU - Sturm, Dominik

AU - Zuckermann, Marc

AU - Witt, Olaf

AU - Bloom, Tabitha

AU - Mitchell, Claire

AU - Miele, Evelina

AU - Colafati, Giovanna Stefania

AU - Diomedi-Camassei, Francesca

AU - Bailey, Simon

AU - Moore, Andrew S

AU - Hassall, Timothy Eg

AU - Lowis, Stephen Paul

AU - Tsoli, Maria

AU - Cowley, Mark J

AU - Ziegler, David S

AU - Karajannis, Matthias A

AU - Aquilina, Kristian

AU - Hargrave, Darren R

AU - Carceller, Fernando

AU - Marshall, Lynley V

AU - von Deimling, Andreas

AU - Kramm, Christof M

AU - Pfister, Stefan M

AU - Sahm, Felix

AU - Baker, Suzanne J

AU - Mastronuzzi, Angela

AU - Carai, Andrea

AU - Vinci, Maria

AU - Capper, David

AU - Popov, Sergey

AU - Ellison, David W

AU - Jacques, Thomas S

AU - Jones, David T W

AU - Jones, Chris

N1 - ©2020 American Association for Cancer Research.

PY - 2020/7

Y1 - 2020/7

N2 - 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 commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.

AB - 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 commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.

U2 - 10.1158/2159-8290.CD-19-1030

DO - 10.1158/2159-8290.CD-19-1030

M3 - SCORING: Journal article

C2 - 32238360

VL - 10

SP - 942

EP - 963

JO - CANCER DISCOV

JF - CANCER DISCOV

SN - 2159-8274

IS - 7

ER -