by ecancer reporter Clare Sansom

Solitary fibrous tumours (SFTs) are rare, often very large mesenchymal tumours that may arise in any soft tissue, although they are most commonly found in the pleural cavity.

About 80% of these tumours are graded as benign on diagnosis.

All solitary fibrous tumours, whether benign or malignant, are treated with complete surgical resection; about two-thirds of patients with malignant tumours will experience at least one recurrence after surgery.

Research published in two papers in the same issue of Nature Genetics has now implicated a fusion between the same two genes, NAB2 and STAT6, in the development of these tumours.

The first study, led by Arul Chinnaiyan from the University of Michigan, Ann Arbor, MI, USA, involved sequencing the exome (protein coding regions of the genome) and the transcriptome from a single patient suffering from recurrent solitary fibrous tumours [1].

The index patient, a 44 year old woman, had been treated for a meningeal malignant SFT in 2002; the cancer recurred in 2009 with tumour masses located in both the brain and the area around the spine.

This patient was enrolled in the Michigan Oncology Sequencing Program MI-ONCOSEQ, a project to sequence tumour genomes and determine so-called “driver” mutations in a range of cancer types.

The morphology of the tumour cells was found to be typical of solitary fibrous tumours, and they stained positive for the adhesion factor CD34, which is also typical for this cancer type.

Next-generation sequencing of tumour and matched normal cells from this patient indicated a total of fourteen non-synonymous point mutations in the tumour genome, with none in the genes that are most frequently mutated in cancer.

Sequencing the RNA transcriptome in the tumour and matched normal cells showed that the most significant chromosomal aberration in the tumour was a fusion between the genes NAB2 and STAT6 on chromosome 12.

On the normal chromosome, these genes are adjacent and are transcribed in opposite directions.

The researchers then analysed the transcriptomes from a total of 27 further cases of SFT from different anatomical sites, and found that all tumours showed this gene fusion to some degree; capillary sequencing of 24 more tumours gave similar results.

Both genes encode transcription factors; the protein product of NAB2 acts in the nucleus to control transcription induced by early growth response proteins, and STAT6 encodes a transcription activator that is activated by growth factors and cytokines.

Immunoblot analysis showed that the protein product of the NAB2-STAT6 fusion gene was expressed in tumour cells from the index case and two other cases.

Over-expression of this fusion protein in cultured tumour cells induced cellular proliferation and activated genes that respond to EGR1.

The second study, by Matthew Meyerson of the Dana-Farber Cancer Institute, Boston, MA, USA and his colleagues, involved sequencing the complete exomes from 17 solitary fibrous tumours and matched normal DNA from the same patients [2].

The average number of non-synonymous somatic mutations observed in these tumours was 22.5.

Chromosome rearrangements resulting in in-frame fusions of the genes NAB2 and STAT6 were observed in seven of the 17 tumour genomes; Meyerson and his colleagues postulated that these were caused by an inversion of part of chromosome 12 that brought the genes together in the same orientation.

This fusion was not observed in any of the matched samples of normal DNA.

Real time PCR of part of this region in cDNA taken from 53 SFT samples taken from 48 affected individuals showed that the NAB2-STAT6 fusion gene was expressed in 55% (29) of them; seven different fusion variants were identified in this sample.

This gene fusion was not observed in samples taken from any other tumour type tested.

Taken together, these results suggest that fusion between the genes NAB2 and STAT6 is a likely driver mutation for solitary fibrous tumours, and that STAT6 inhibitors might be effective in recurrent, malignant cases of this tumour, which are poorly treated by surgery alone.

References

[1] Robinson, D.R., Wu, Y-M., Kalyana-Sundaram, S. and 18 others (2013). Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nature Genetics, published online ahead of print 13 January 2013. doi:10.1038/ng.2509

[2] Chmielecki, J., Crago, A.M., Rosenberg, M. and 8 others (2013). Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nature Genetics, published online ahead of print 13 January 2013. doi:10.1038/ng.2522