Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail

Abstract

Primary brain tumors occur in 8 out of 100 000 people and are the leading cause of cancer-related death in children. Among brain tumors, high-grade astrocytomas (HGAs) including glioblastoma multiforme (GBM) are aggressive and are lethal human cancers. Despite decades of concerted therapeutic efforts, HGAs remain essentially incurable in adults and children. Recent discoveries have revolutionized our understanding of these tumors in children and young adults. Recurrent somatic driver mutations in the tail of histone 3 variant 3 (H3.3), leading to amino acid substitutions at key residues, namely lysine (K) 27 (K27M) and glycine 34 (G34R/G34V), were identified as a new molecular mechanism in pediatric GBM. These mutations represent the pediatric counterpart of the recurrent mutations in isocitrate dehydrogenases (IDH) identified in young adult gliomas and provide a much-needed new pathway that can be targeted for therapeutic development. This review will provide an overview of the potential role of these mutations in altering chromatin structure and affecting specific molecular pathways ultimately leading to gliomagenesis. The distinct changes in chromatin structure and the specific downstream events induced by each mutation need characterizing independently if progress is to be made in tackling this devastating cancer.

Figure 1

Neuroanatomical and age specificity of isocitrate dehydrogenase (IDH), K27M‐H3.3 and G34R/V‐H3.3 mutations in high‐grade astrocytomas (HGA). K27M‐H3.3 or H3.1 (yellow stars) occur mainly in brainstem HGA and K27M‐H3.3 mainly thalamic HGA (70%–80% of all GBM in these locations). This H3.3 mutation is inconsistently associated with ATRX mutations. G34R/V‐H3.3 occur mainly in the cerebral hemispheres similar to IDH mutations which have been previously shown to have a predilection for the frontal cortex. Both H3.3 mutations are significantly associated with ATRX mutations (purple filled circles) and TP53 mutations (not represented here for clarity issues). IDH and H3.3 mutations represent distinct disease entities that possibly arise from separate cellular origins as the result of largely non‐overlapping sets of molecular events. Note: the size of the shape illustrating each mutation is approximately proportional to the % identified in 34, 59, 62.