Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Centre for Computational Medicine The Hospital for Sick Children Toronto ON Canada

Children's Cancer Center National Center for Child Health and Development Tokyo Japan

Children's Cancer Centre Royal Children's Hospital Melbourne Australia

Department of Anatomic Pathology Dalhousie University Halifax NS Canada

Department of Hematology and Oncology The Hospital for Sick Children Toronto ON Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada

Department of Laboratory Medicine and Pathology University of Alberta Edmonton AB Canada

Department of Medical Biophysics University of Toronto Toronto ON Canada

Department of Medicine McGill University Montreal QC Canada

Department of Neurosurgery Kyorin University Faculty of Medicine Tokyo Japan

Department of Neurosurgery The Hospital for Sick Children Toronto ON Canada

Department of Oncology and Children's Research Center University Children's Hospital Zurich Zurich Switzerland

Department of Pathology and Laboratory Medicine Nationwide Children's Hospital Columbus OH USA

Department of Pathology and Laboratory Medicine The University of British Columbia Vancouver BC Canada

Department of Pathology and Laboratory Medicine University of Ottawa Ottawa ON Canada

Department of Pathology Hospital Universitario Niño Jesús Madrid Spain

Department of Pathology Laboratory Medicine IWK Health Centre Halifax NS Canada

Department of Pathology The Ohio State University College of Medicine Columbus OH USA

Department of Pathology University Hospital de São João Porto Portugal

Department of Pediatric Hematology and Oncology Hospital Universitario Niño Jesús Madrid Spain

Department of Pediatric Laboratory Medicine The Hospital for Sick Children Toronto ON Canada

Department of Pediatric Neurosurgery Osaka City General Hospital Osaka Japan

Department of Pediatric Oncology Hospital Cruces Bilbao Spain

Department of Pediatric Oncology Hospital Infantil Virgen del Rocio Sevilla Spain

Department of Pediatric Oncology Hospital Sant Joan de Déu Barcelona Spain

Department of Pediatrics The University of British Columbia Vancouver BC Canada

Department of Pediatrics University of Alberta Edmonton AB Canada

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON Canada

Division of Anatomic Pathology British Columbia Children's Hospital Vancouver BC Canada

Division of Brain Tumor Translational Research National Cancer Center Research Institute Tokyo Japan

Division of Hematology Oncology BMT British Columbia Children's Hospital Vancouver BC Canada

Division of Hematology Oncology Bone Marrow Transplantation Nationwide Children's Hospital Columbus OH USA

Division of Hematology Oncology Children's Hospital of Eastern Ontario Ottawa ON Canada

Division of Hematology Oncology IWK Health Centre Halifax NS Canada

Division of Neurosurgery Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon Portugal

Division of Neurosurgery IWK Health Centre Halifax NS Canada

Division of Pediatric Hematology Oncology Mayo Clinic Rochester MN USA

Division of Pediatric Hematoncology University Hospital de São João Porto Portugal

Institute of Neuropathology University Hospital Zurich Zurich Switzerland

Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina Universidade de Lisboa Lisbon Portugal

Murdoch Children's Research Institute Department of Paediatrics University of Melbourne Melbourne Australia

The Arthur and Sonia Labatt Brain Tumor Research Centre The Hospital for Sick Children Toronto ON Canada

The Department of Pediatric Hematology Oncology Hadassah Medical Center Jerusalem Israel

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