Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Scott Ryall; Michal Zapotocky; Kohei Fukuoka; Liana Nobre; Ana Guerreiro Stucklin; Julie Bennett; Robert Siddaway; Christopher Li; Sanja Pajovic; Anthony Arnoldo; Paul E Kowalski; Monique Johnson; Javal Sheth; Alvaro Lassaletta; Ruth G Tatevossian; Wilda Orisme; Ibrahim Qaddoumi; Lea F Surrey; Marilyn M Li; Angela J Waanders; Stephen Gilheeney; Marc Rosenblum; Tejus Bale; Derek S Tsang; Normand Laperriere; Abhaya Kulkarni; George M Ibrahim; James Drake; Peter Dirks; Michael D Taylor; James T Rutka; Suzanne Laughlin; Manohar Shroff; Mary Shago; Lili-Naz Hazrati; Colleen D'Arcy; Vijay Ramaswamy; Ute Bartels; Annie Huang; Eric Bouffet; Matthias A Karajannis; Mariarita Santi; David W Ellison; Uri Tabori; Cynthia Hawkins

doi:10.1016/j.ccell.2020.03.011

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Cancer Cell. 2020 Apr 13;37(4):569-583.e5. doi: 10.1016/j.ccell.2020.03.011.

Authors

Scott Ryall¹, Michal Zapotocky², Kohei Fukuoka³, Liana Nobre³, Ana Guerreiro Stucklin⁴, Julie Bennett³, Robert Siddaway⁵, Christopher Li¹, Sanja Pajovic⁵, Anthony Arnoldo⁶, Paul E Kowalski⁶, Monique Johnson⁶, Javal Sheth⁷, Alvaro Lassaletta⁸, Ruth G Tatevossian⁹, Wilda Orisme⁹, Ibrahim Qaddoumi¹⁰, Lea F Surrey¹¹, Marilyn M Li¹², Angela J Waanders¹³, Stephen Gilheeney¹⁴, Marc Rosenblum¹⁵, Tejus Bale¹⁵, Derek S Tsang¹⁶, Normand Laperriere¹⁶, Abhaya Kulkarni¹⁷, George M Ibrahim¹⁷, James Drake¹⁷, Peter Dirks¹⁸, Michael D Taylor¹⁸, James T Rutka¹⁸, Suzanne Laughlin¹⁹, Manohar Shroff¹⁹, Mary Shago²⁰, Lili-Naz Hazrati²¹, Colleen D'Arcy²², Vijay Ramaswamy²³, Ute Bartels²⁴, Annie Huang²⁵, Eric Bouffet²⁴, Matthias A Karajannis¹⁴, Mariarita Santi¹¹, David W Ellison⁹, Uri Tabori²⁶, Cynthia Hawkins²⁷

Affiliations

¹ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
² Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
⁶ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatric Hematology and Oncology, Hospital Universitario Niño Jesús, Madrid, Spain.
⁹ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹⁰ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹³ Department of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA; Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
¹⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.
¹⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.
¹⁹ Department of Radiology, The Hospital for Sick Children, Toronto ON, Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
²⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
²¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
²² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Anatomical Pathology, The Alfred Hospital, Prahran, VIC, Australia.
²³ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
²⁶ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
²⁷ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: cynthia.hawkins@sickkids.ca.

Abstract

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

Keywords: RAS/MAPK pathway; brain tumor; low-grade glioma; molecular diagnostics; neurooncology; pediatric; risk stratification.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Biomarkers, Tumor / genetics*
Brain Neoplasms / classification
Brain Neoplasms / genetics*
Brain Neoplasms / pathology
Child
Child, Preschool
Cohort Studies
DNA Copy Number Variations*
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Gene Rearrangement*
Glioma / classification
Glioma / genetics*
Glioma / pathology
Humans
Infant
Infant, Newborn
Male
Mitogen-Activated Protein Kinases / genetics
Mutation*
Neurofibromin 1 / genetics
Oncogene Proteins, Fusion / genetics
Proto-Oncogene Proteins B-raf / genetics
ras Proteins / genetics

Substances

BRAF-KIAA1549 fusion protein, human
Biomarkers, Tumor
NF1 protein, human
Neurofibromin 1
Oncogene Proteins, Fusion
BRAF protein, human
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinases
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding