by ecancer reporter Clare Sansom

Craniopharyngiomas are rare brain tumours that arise from the embryonic tissue of the pituitary gland.

They can develop at any age but principally occur in childhood and middle age; the adamantinomatous subtype is more common in children and the papillary subtype in adults.

They are slow growing and are generally classed as benign, but they are difficult to treat and both the tumour and its treatment can cause significant morbidity including severe headaches and visual disturbances.

There are few pharmaceutical options available; the main treatment is surgery, which is complicated by the location of the tumour at the base of the skull near the hypothalamus and pituitary glands.

Adamantinomatous craniopharyngiomas have been linked to mutations in the gene CTNNB1, which codes for β-catenin, but very little is known about the genetic drivers of the papillary subtype of this tumour.

A large group of researchers led by Gad Getz of the Broad Instititute of MIT and Harvard, Cambridge, Massachusetts, USA and Sandro Santagata of Brigham and Women's Hospital, Boston, Massachusetts, USA have now conducted an extensive whole-exome sequencing study of both subtypes of craniopharyngioma in order to identify driver mutations.

Initially, the researchers sequenced the exomes of a discovery cohort of 12 adamantinomatous and three papillary craniopharyngiomas.

All tumours in both subtypes had relatively few non-synonymous somatic mutations compared to many other tumour types, which is consistent with the classification of the tumour as benign.

As in previous studies, CTNNB1 was found to be the most frequently mutated gene in the adamantinomatous craniopharyngiomas; almost all (11/12) of these tumours had mutations in this gene.

Many other genes were found to be mutated in at least one adamantinomatous tumour; many of these have been previously implicated in cancer and are known to encode proteins that are involved in transcriptional regulation, epigenetic regulation and DNA repair.

All three papillary craniopharyngiomas sequenced were found to carry a mutation in the oncogene BRAF leading to a change from valine to glutamic acid at position 600 of the encoded protein (V600E).

This mutation, which is common in many tumour types, is known to constitutively activate the B-Raf protein causing it to continually drive cells round the cell cycle.

None of the papillary craniopharyngiomas harboured mutations in CTNNB1.

The researchers validated these results using targeted genotyping and immuno-histochemistry with an additional 98 tumour samples (39 papillary and 59 adamantinomatous craniopharyngiomas).

Mutations in CTNNB1 were found in 51 (96%) of 53 adamantinomatous tumours and in none of the papillary tumours tested; the β-catenin protein was found to be located in the cytoplasm and nucleus of the adamantinomatous tumours, but exclusively in the cytoplasmic membrane (as is normal) in the papillary tumours.

Furthermore, and remarkably, 34 (94.4%) of 36 papillary tumours were found to carry BRAF mutations that caused changes to the amino acid at position 600 of the protein sequence; no BRAF mutations were observed in the adamantinomatous tumours.

Both these mutations were found to be clonal: that is, if a mutation was present it could be found in all tumour cells tested,

Taken together, these results validate the identification of mutations in CTNNB1 as drivers for adamantinomatous craniopharyngiomas and identify BRAF mutations for the first time as drivers for the papillary subtype of these tumours.

The extremely high frequency of mutations in these two genes, the mutual exclusivity of these mutations and the relatively low numbers of other mutated genes in the tumours all suggest that agents directed against mutated β-catenin and B-Raf could be important therapeutic options for these tumours.

Patients with papillary tumours, in particular, are likely to benefit from vemurafenib, which was licensed in 2012 for treating melanomas bearing mutations at amino acid position 600.

It is also likely that tests for these mutations could be a useful diagnostic tool for distinguishing between craniopharyngioma subtypes.

Reference

Brastianos, P.K., Taylor-Weiner, A., Manley, P.E. and 31 others (2014). Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nature Genetics, published online ahead of print 12 January 2014. doi:10.1038/ng.2868