Ahmed Gilani1,2, Andrew Donson3, Kurtis D Davies4, Susan L Whiteway5,6, Jessica Lake7, John DeSisto8, Lindsey Hoffman3, Nicholas K Foreman3, B K Kleinschmidt-DeMasters9, Adam L Green3,8. 1. Department of Pathology, Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. ahmed.gilani@childrenscolorado.org. 2. Department of Pathology, School of Medicine, University of Colorado, 13123 East 16th Avenue, Box 120, Aurora, CO, 80045, USA. ahmed.gilani@childrenscolorado.org. 3. The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA. 4. Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. 5. Department of Pediatrics, Brooke Army Medical Center, San Antonio, TX, USA. 6. Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 7. Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA. 8. The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA. 9. Departments of Pathology, Neurology, Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Abstract
INTRODUCTION: Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored. METHODS: Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study. RESULTS: Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults. CONCLUSIONS: Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.
INTRODUCTION:Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored. METHODS: Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study. RESULTS: Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults. CONCLUSIONS: Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.
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