Dataset Information

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

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

SUBMITTER: Clarke M

PROVIDER: S-EPMC8313225 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Clarke Matthew M Mackay Alan A Ismer Britta B Pickles Jessica C JC Tatevossian Ruth G RG Newman Scott S Bale Tejus A TA Stoler Iris I Izquierdo Elisa E Temelso Sara S Carvalho Diana M DM Molinari Valeria V Burford Anna A Howell Louise L Virasami Alex A Fairchild Amy R AR Avery Aimee A Chalker Jane J Kristiansen Mark M Haupfear Kelly K Dalton James D JD Orisme Wilda W Wen Ji J Hubank Michael M Kurian Kathreena M KM Rowe Catherine C Maybury Mellissa M Crosier Stephen S Knipstein Jeffrey J Schüller Ulrich U Kordes Uwe U Kram David E DE Snuderl Matija M Bridges Leslie L Martin Andrew J AJ Doey Lawrence J LJ Al-Sarraj Safa S Chandler Christopher C Zebian Bassel B Cairns Claire C Natrajan Rachael R Boult Jessica K R JKR Robinson Simon P SP Sill Martin M Dunkel Ira J IJ Gilheeney Stephen W SW Rosenblum Marc K MK Hughes Debbie D Proszek Paula Z PZ Macdonald Tobey J TJ Preusser Matthias M Haberler Christine C Slavc Irene I Packer Roger R Ng Ho-Keung HK Caspi Shani S Popović Mara M Faganel Kotnik Barbara B Wood Matthew D MD Baird Lissa L Davare Monika Ashok MA Solomon David A DA Olsen Thale Kristin TK Brandal Petter P Farrell Michael M Cryan Jane B JB Capra Michael M Karremann Michael M Schittenhelm Jens J Schuhmann Martin U MU Ebinger Martin M Dinjens Winand N M WNM Kerl Kornelius K Hettmer Simone S Pietsch Torsten T Andreiuolo Felipe F Driever Pablo Hernáiz PH Korshunov Andrey A Hiddingh Lotte L Worst Barbara C BC Sturm Dominik D Zuckermann Marc M Witt Olaf O Bloom Tabitha T Mitchell Clare C Miele Evelina E Colafati Giovanna Stefania GS Diomedi-Camassei Francesca F Bailey Simon S Moore Andrew S AS Hassall Timothy E G TEG Lowis Stephen P SP Tsoli Maria M Cowley Mark J MJ Ziegler David S DS Karajannis Matthias A MA Aquilina Kristian K Hargrave Darren R DR Carceller Fernando F Marshall Lynley V LV von Deimling Andreas A Kramm Christof M CM Pfister Stefan M SM Sahm Felix F Baker Suzanne J SJ Mastronuzzi Angela A Carai Andrea A Vinci Maria M Capper David D Popov Sergey S Ellison David W DW Jacques Thomas S TS Jones David T W DTW Jones Chris C

Cancer discovery 20200401 7

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 spe ...[more]

PMID: 32238360

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Project description:Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with 'paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

Dataset Information

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

Publications

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

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