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

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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 37 Issue 4 Pg. 569-583.e5 (04 13 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 32289278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• Adolescent
• Biomarkers, Tumor (genetics)
• Brain Neoplasms (classification, genetics, pathology)
• Child
• Child, Preschool
• Cohort Studies
• DNA Copy Number Variations
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Rearrangement
• Glioma (classification, genetics, 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)