TY - JOUR
T1 - Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumormutational burden, and hypermutation signatures
AU - Johnson, Adrienne
AU - Severson, Eric
AU - Gay, Laurie
AU - Vergilio, Jo Anne
AU - Elvin, Julia
AU - Suh, James
AU - Daniel, Sugganth
AU - Covert, Mandy
AU - Frampton, Garrett M.
AU - Hsu, Sigmund
AU - Lesser, Glenn J.
AU - Stogner-Underwood, Kimberly
AU - Mott, Ryan T.
AU - Rush, Sarah Z.
AU - Stanke, Jennifer J.
AU - Dahiya, Sonika
AU - Sun, James
AU - Reddy, Prasanth
AU - Chalmers, Zachary R.
AU - Erlich, Rachel
AU - Chudnovsky, Yakov
AU - Fabrizio, David
AU - Schrock, Alexa B.
AU - Ali, Siraj
AU - Miller, Vincent
AU - Stephens, Philip J.
AU - Ross, Jeffrey
AU - Crawford, John R.
AU - Ramkissoon, Shakti H.
N1 - Publisher Copyright:
© 2017, AlphaMed Press. All rights reserved.
PY - 2017/12
Y1 - 2017/12
N2 - 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.
AB - 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.
KW - Clinical sequencing
KW - Glioma
KW - Immunotherapy
KW - Pediatric neuro-oncology
KW - Precision medicin
UR - http://www.scopus.com/inward/record.url?scp=85035077600&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2017-0242
DO - 10.1634/theoncologist.2017-0242
M3 - Article
C2 - 28912153
AN - SCOPUS:85035077600
SN - 1083-7159
VL - 22
SP - 1478
EP - 1490
JO - Oncologist
JF - Oncologist
IS - 12
ER -