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

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

TLDR

  • Infant high-grade gliomas have distinct biological characteristics that differ from those in older children.
  • Researchers identified novel subgroups of infant gliomas with targetable genetic alterations, which may respond better to specific treatments.
  • This study promotes a paradigm shift in the diagnosis and management of infant gliomas, emphasizing the need for personalized treatment approaches.

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(= 31),(= 21),(= 9), and(= 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, orgene 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...

Overview

  • The study aims to investigate the biological differences between infant high-grade gliomas and their counterparts in older children.
  • The researchers collected 241 cases of infant gliomas under 4 years of age, with histologic review, methylation profiling, and custom panel, genome, or exome sequencing.
  • The primary objective is to identify the distinct characteristics and subgroups of infant gliomas, and to determine the most effective diagnostic and management strategies.

Comparative Analysis & Findings

  • The study identified 130 cases of infant gliomas as part of an 'intrinsic' spectrum of disease specific to the infant population.
  • The most common driving alterations were targetable MAPK alterations, gene fusions targeting (31%), (21%), (9%), and (4%), with evidence of efficacy of targeted agents in the clinic.
  • The study found that kinase fusion-positive tumors had a better outcome and responded to targeted therapy clinically, while fusion-negative cases had a poor outcome and may represent an epigenetically driven pluripotent stem cell phenotype.

Implications and Future Directions

  • The study suggests that infant gliomas require a change in diagnostic practice and management due to their unique biology and distinct subgroups.
  • Future studies could investigate the molecular mechanisms underlying these subgroups, and explore the development of targeted therapies for the treatment of infant gliomas.
  • A deeper understanding of the epigenetic and genetic drivers of infant gliomas could lead to the development of more effective and personalized treatment strategies for this patient population.
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