Genetic Analysis of Diffuse High‐Grade Astrocytomas in Infancy Defines a Novel Molecular Entity

Abstract

Pediatric high‐grade gliomas are considered to be different when compared to adult high‐grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high‐grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high‐grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe‐dependent amplification (MLPA), pyrosequencing of glioma‐associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high‐grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high‐grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior.