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

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

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.

Presented By Scott Ryall