Around 1 in 3 patients with the most common form of kidney cancer carry mutations in the PBRM1 gene, finds a paper in Nature. The collaboration between UK, US and Singapore researchers, strengthens the relationship between clear cell renal cell carcinoma (ccRCC) and aberrant chromatin biology, pointing the way forward for further research.
Until now the genetics of ccRCC have been dominated by inactivation of the VHL tumour suppressor gene, found on chromosome 3, which has been shown to be mutated in 8 out of 10 patients. But studies have demonstrated that VHL loss alone is insufficient for ccRCC tumorigenesis, suggesting that additional genetic mutations must be involved.
"So the question we have sought to answer is which genes are conspiring with VHL to cause the disease we see in patients?" said Andrew Futreal, co-Head of the Cancer Genome Project at the Wellcome Trust Sanger Institute (Hinxton, UK), who took part in the UK arm of the study. In separate publications the team have recently identified three mutated genes associated with renal cancer (UTX, JARID1C and SETD2) that are all involved in altering chromatin (the scaffold that holds DNA together in cells and influences gene activity).
In the current study, investigators from the Wellcome Trust Sanger Institute, the Van Andel Research Institute, USA, and the National Cancer Centre of Singapore, obtained DNA samples from 257 patients with ccRCC, finding that the gene PBRM1 (also known as Baf180) was mutated in 88 cases. Interestingly, the PBRM1 gene is known to function as part of a protein complex called SW1-SNF, which also acts to alter the structure of chromatin. The results, say investigators, can be seen as a further indication of the importance of aberrant chromatin biology in ccRCC. Furthermore, the investigators found that the PBRM1 gene is found on chromosome 3 and located close to the VHL cancer gene and the recently identified SETD2 gene.
"Our understanding of the disease has been transformed by the realisation that most of these genes are involved in providing the structure that encases DNA in the cell and that regulates its function. This insight will provide us with many new therapeutic directions for this cancer," said Mike Stratton, Director of the Sanger Institute.
Reviewing results of several insertional mutagenesis screens carried out in mice, the team believe that PBRM1 also plays a role in pancreatic cancers, cooperating with Kras to drive tumour development. "This finding reinforces the need to define cancer not just by the organ, but also by the mutational profile of individual patients," said David Adams, also from the Sanger Institute.
I Varela, P Tarpey, K Raine et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. Doi: 10.1038/nature09639
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