Mutations that are specifically associated with the paediatric forms of glioblastoma — a lethal brain tumour -- are identified in Nature and Nature Genetics this week. The reports suggest pathways that may be involved in the development of glioblastoma in young individuals. The discovery of such disease-relevant targets is crucial to aid the design of new therapeutic agents, given that conventional glioblastoma treatments universally fail.

Adult and paediatric glioblastoma are thought to be caused by largely different genetic alterations, but paediatric cases are less well characterized than adult disease. To address this imbalance, Nada Jabado and co-workers performed exome sequencing of 48 childhood glioblastoma samples; their work is reported in Nature.

They identify somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway, which is responsible for remodelling of genetic material in chromosomes, in 44% of tumours. Mutations in H3F3A, which encodes histone 3 variant H3.3, were found in 31% of tumours. Histone H3 is responsible for organizing the DNA of every cell in the body and also for regulating the expression of the DNA code during normal development.

Paediatric diffuse intrinsic pontine glioma (DIPG, a childhood cancer of brain stem glia) has a long-term survival rate of less than one in ten and is usually inoperable because the brain stem controls essential functions such as breathing. Suzanne Baker and co-workers report in Nature Genetics the whole-genome sequencing of DNA from DIPGs and matched germline tissues from seven affected individuals, identifying somatic mutations in two genes coding for histones H3.1 and H3.3. In following targeted sequencing in a validation cohort, these mutations were identified in 39 out of 50 paediatric DIPGs and 13 out of 36 non-brainstem paediatric glioblastomas.

The mutations identified in these studies are shown to be specific to glioblastoma and highly prevalent in children and young adults. These results suggest that changes affecting chromatin architecture may be the cause of disease in this population of paediatric glioblastoma patients. In addition, this is the first time that histone 3 variant H3.3 has been implicated in tumour development.

Source: Nature