Clear cell kidney cancer gene mutation identified in multicenter study

March 3, 2011

In a collaborative project involving scientists from three continents, researchers have identified a gene that is mutated in one in three patients with the most common form of renal cancer.

In a collaborative project involving scientists from three continents, researchers have identified a gene that is mutated in one in three patients with the most common form of renal cancer.

The gene, called PBRM1, was found to be mutated in 88 cases out of 257 clear cell renal cell carcinomas analyzed, making it the most prevalent to be identified in renal cancer in 20 years.

The study, published in Nature (2011; 469:539-42), was carried out by researchers from the Wellcome Trust Sanger Institute, Hinxton, United Kingdom, the National Cancer Centre of Singapore, and the Van Andel Research Institute, Grand Rapids, MI.

"Until recently, when we talked about the genetics of renal carcinoma we would inevitably be talking about VHL, a gene mutated in eight out of 10 patients," said co-author Andy Futreal, PhD, of the Wellcome Trust Sanger Institute. "But we knew this was likely not to be the full story, so the question we have sought to answer is which genes are conspiring with VHL to cause the disease we see in patients?"

"Our understanding of how kidney cancer develops had already markedly improved through identification of three new mutated cancer genes, each of which makes a small contribution to the disease," added co-author Mike Stratton, PhD, of the Wellcome Trust Sanger Institute. "Now, our discovery of PBRM1 mutations in one in three kidney cancers is a major advance. We think we may have an almost complete understanding of the set of abnormal genes that drive this cancer, and our understanding of the disease has been transformed by the realization 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."

Much of the story, the researchers suggest, seems to be locked into a small region of chromosome 3. The study found that PBRM1 is tied together with two previously identified renal cancer genes, including the well-established VHL cancer gene and the recently identified gene SETD2, on a small region of chromosome 3.

The team suggests that the fact that the genes are linked in their location allows cancer to exploit human biology-by reducing the number of genetic events needed to hit and inactivate all three genes. The team found a significant level of overlap, with many patients carrying mutations in two, if not all three of the genes in this region.