by ecancer reporter Clare Sansom

In children, brain tumours are more common than any other type of solid tumour; they also account for more deaths in childhood than any other cancer type.

The range of brain tumour subtypes that affect children differs from that found in the adult population.

Few drugs are available to treat childhood brain tumours, and other treatment options are often very limited due to the location of the tumours.

Research presented in four papers published simultaneously in the journal Nature Genetics has implicated mutations in the gene AVCR1 in the development of two deadly types of paediatric brain tumour.

This gene encodes a protein known as AVCR1 or ALK-2, which is a transmembrane receptor that passes signals into cells when bound by the growth factor activin; this activates the transcription of a specific set of genes.

Three of these studies concern diffuse intrinsic pontine glioma (DIPG), which arises in the brainstem.

About 10-15% of children diagnosed with a cancer of the CNS will have this tumour type, which cannot be treated with surgery and which is almost universally fatal.

Recently, several independent studies have noted mutations in histone variants H3.3 or H3.1 in this tumour type that cause a lysine to be substituted by a methionine (p.Lys27Met) and which is likely to cause profound changes in gene expression patterns.

This finding indicates that epigenetic as well as genetic changes are involved in the development of these tumours.

A group of researchers led by Cynthia Hawkins of the Hospital for Sick Children, Toronto, Ontario, Canada used whole-genome sequencing with analysis of methylation, gene expression and copy number to determine the genetic profiles of DIPG samples from 36 children [1].

Twenty of the samples were analysed using whole genome sequencing of paired tumour and normal brain tissue, and the other 16 using whole exome sequencing.

Clustering the samples based on their methylation profiles divided them clearly into three subgroups, named ‘MYCN’, ‘silent’ and ‘H3-K27M’.

The MYCN subgroup was characterised by hyper-methylation leading to over-expression of MYCN and ID2 but had no recurrent mutations; the silent subgroup had the fewest mutations overall, and the H3-K27M subgroup had unstable genomes with mutations in many genes including those encoding histones.

Mutations in AVCR1 were found in 20% of the 36 cases, including tumours from all three subgroups.

These mutations were found to constitutively activate the ACVR1 protein, leading to the increased expression of the targets of this signalling pathway, ID1 and ID2.

Two separate studies led by Suzanne Baker from St. Jude Children’s Research Hospital, Memphis, TN, USA [2] and Chris Jones from the Institute of Cancer Research, Sutton, Surrey, UK [3] respectively found similar results in independent tumour sample sets from DIPG patients.

Baker and her co-workers used whole-genome, exome and transcriptome sequencing to analyse mutations in 57 DIPGs and 70 paediatric high grade gliomas that arose outside the brainstem.

They discovered recurrent somatic mutations in ACVR1 in 32% of DIPG cases but in none of the other gliomas; this was the only gene in which recurrent mutations were exclusively associated with one of the tumour types.

Tumours carrying ACVR1 mutations were associated with a younger age at diagnosis, a longer survival time and histone mutations causing the p.Lys27Met substitution.

Jones and his colleagues used whole-genome sequencing to analyse pre-treatment biopsies obtained from 20 DIPG patients and whole-exome sequencing to analyse 5 samples obtained at autopsy and one further biopsy sample. 

They identified somatic mutations in the ACVR1 gene in seven of the 26 samples, giving rise to six different substitutions at four different amino acid positions.

They noted further that although none of these mutations had been previously associated with cancer, they had all been found in the germlines of individuals with a developmental disorder, fibrodysplasia ossificans progressiva.

This extremely rare condition, which is known colloquially as Stone Man Syndrome causes muscles, tendons and ligaments to turn gradually into bone.

The fourth study in this series, by Nada Jabado of McGill University, Montreal, Quebec, Canada and her co-workers, found mutations in the same gene in a different type of paediatric brain tumour, midline high-grade astrocytoma (mHGA) [4].

Like DIPG, this tumour type is exceptionally difficult to treat; it has also recently been associated with histone mutations that lead to the p.Lys27Met substitution.

Jabado and his colleagues analysed 40 mHGA samples, mainly using whole exome sequencing, and observed somatic AVCR1 mutations in five (12.5%) of these cases, all associated with the histone p.Lys27Met substitution.

All the AVCR1 mutations were classified as gain-of-function mutations.

Taken together, these results implicate activating mutations in AVCR1 in a significant subset of two important and intractable types of paediatric brain tumour, and suggest that the protein AVCR1 might be a useful drug target for these tumours.

References

[1] Buczkowicz, P., Hoeman, C., Rakopoulos, P. and 49 others (2014). Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nature Genetics, published online ahead of print 6 April 2014.

[2] Wu, G., Diaz, A.K., Paugh, B.S. and 44 others, for the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project (2014). The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics, published online ahead of print 6 April 2014. 

[3] Taylor, K.R., Mackay, A., Truffaux, N. and 20 others (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nature Genetics, published online ahead of print 6 April 2014.

[4] Fontebasso, A.M., Papillon-Cavanagh, S., Schwartzentruber, J. and 45 others (2014). Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nature Genetics, published online ahead of print 6 April 2014.