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 (ccRCC) analysed, making it the most prevalent to be identified in renal cancer in 20 years.
The identification of a frequently mutated gene provides new insights into the biology of the disease, which will be critical in the continued effort to improve treatment for renal cancer. The study, published today in the journal Nature, was carried out by researchers from the Wellcome Trust Sanger Institute (UK), the National Cancer Centre of Singapore, and Van Andel Research Institute (VARI) of Grand Rapids, Michigan.
Renal cancer is among the 10 most common cancers in both men and women in the United States, striking nearly 60,000 Americans in 2010, and killing more than 13,000, according to the National Cancer Institute.
Renal cell carcinoma (RCC) accounts for 9 out of 10 kidney cancers, and ccRCC is the most common subtype, accounting for 8 out of 10 RCC cases. Survival rates for early-detected ccRCC tumors can be as high as 95 percent, but that prognosis falls over time as tumors develop. Diagnosis is complicated by the fact that tumors can grow in the kidney for some time without presenting symptoms.
For many years, the main genetic determinant known to be involved in the development of renal carcinoma was mutation of the VHL gene on chromosome 3.
"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 ten patients," said Dr. Andy Futreal, Head of Cancer Genetics and Genomics and co-Head of the Cancer Genome Project at 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?"
"Over the last year or so, we have started to assemble that puzzle – this research provides a new and critical piece."
The team's recent work had previously identified three mutated genes associated with renal cancer. These genes are all involved in altering part of the scaffold – known as chromatin – that holds the DNA together in our cells and can influence gene activity.
"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" said Professor Mike Stratton, Director of the Sanger Institute and co-Head of the Cancer Genome Project. "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 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."
Much of the story, the researchers suggest, seems to be locked into a small region of chromosome 3. The study finds that PBRM1(also known as Baf180) 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 our 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.
"This study has begun to unlock the way these latest gene discoveries contribute to cancer," said Professor Bin Tean Teh, M.D., Ph.D., Head of the Van Andel Research Institute Laboratory for Cancer Genetics and the NCSS-VARI Translational Research Laboratory at the National Cancer Centre of Singapore. "And it is to the cancer's advantage that they sit together. The challenge for the future will be to build a picture of the processes the genes control. That will mean looking beyond the linear DNA code to the chemical interactions that take place at the structural level – at the level of the chromosome."
Importantly, the newly discovered gene, PBRM1, functions as part of a protein complex called SWI-SNF, which also acts to alter the structure of chromatin – further pointing to the importance of genome regulation in renal cancer.
"Our work provides evidence that PBRM1 may affect the processes of cell division in renal cells. Therefore, a defect in this gene could lead to abnormal cellular growth," said Kyle Furge, Ph.D., Head of VARI's Laboratory of Computational Biology. "For researchers, this discovery is exciting because PBRM1 is a protein that modifies the DNA in the cell. This study is one of the first to show that proteins that modify DNA are frequently mutated in cancer."
The mutations all appear to inactivate a protein that plays a role in remodelling the structure of the genetic material, allowing access of the DNA code to other proteins that can repair damage, control cell growth and turn other genes on and off.
In addition to the PBRM1 mutations, the team also found mutations in a gene called ARID1A in some ccRCC cases. The same gene was identified just weeks ago in clear cell ovarian cancer. The researchers suggest that further larger-scale research will be needed to understand what role this second gene plays in renal cancer.
Notes to Editors
Publication DetailsVarela I et al. (2010) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature.
Published online before print at doi: 10.1038/nature09639
This work was supported by the Wellcome Trust, the Van Andel Research Institute, the Lee Foundation, Cancer Research UK, the University of Cambridge and a fellowship from The International Human Frontier Science Program Organization.
Participating CentersCancer Genome Project, Bioinformatics and Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
About Van Andel Institute
Established by Jay and Betty Van Andel in 1996, Van Andel Institute (VAI) is an independent research and educational organization based in Grand Rapids, Mich., dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process. VARI, the research arm of VAI, is dedicated to probing the genetic, cellular and molecular origins of cancer, Parkinson and other diseases and working to translate those findings into effective therapies. VARI is affiliated with the Translational Genomics Research Institute, (TGen), of Phoenix, Arizona. http://www.vai.org
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease. http://www.sanger.ac.uk
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. http://www.wellcome.ac.uk
Joe Gavan | EurekAlert!
Further reports about: > Cancer > Cancer Genetics > Computational Biology > Computational Neuroscience > DNA > DNA code > Genetics > Genom > Genomics > Nature Immunology > PBRM1 > RCC > Translational Research > VARI > cancer gene > cell carcinoma > chromosome 3 > kidney cancer > mutated gene > synthetic biology
Multi-year study finds 'hotspots' of ammonia over world's major agricultural areas
17.03.2017 | University of Maryland
Diabetes Drug May Improve Bone Fat-induced Defects of Fracture Healing
17.03.2017 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy