Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumormutational burden, and hypermutation signatures

Adrienne Johnson, Eric Severson, Laurie Gay, Jo Anne Vergilio, Julia Elvin, James Suh, Sugganth Daniel, Mandy Covert, Garrett M. Frampton, Sigmund Hsu, Glenn J. Lesser, Kimberly Stogner-Underwood, Ryan T. Mott, Sarah Z. Rush, Jennifer J. Stanke, Sonika Dahiya, James Sun, Prasanth Reddy, Zachary R. Chalmers, Rachel ErlichYakov Chudnovsky, David Fabrizio, Alexa B. Schrock, Siraj Ali, Vincent Miller, Philip J. Stephens, Jeffrey Ross, John R. Crawford, Shakti H. Ramkissoon

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Background. Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating nextgeneration sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can informdiagnostic, prognostic, and therapeutic decision-making. Materials and Methods. We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). Results. In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF, QKI-RAF1, FGFR3-TACC3, CEP85L-ROS1, and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M.Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4-ALK, DGKB-ETV1, ATG7-RAF1, and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations perMb; range 43–581 mutations perMb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases). Conclusion. Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy.

Original languageEnglish
Pages (from-to)1478-1490
Number of pages13
JournalOncologist
Volume22
Issue number12
DOIs
StatePublished - Dec 2017

Keywords

  • Clinical sequencing
  • Glioma
  • Immunotherapy
  • Pediatric neuro-oncology
  • Precision medicin

Fingerprint

Dive into the research topics of 'Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumormutational burden, and hypermutation signatures'. Together they form a unique fingerprint.

Cite this