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
The importance of biodiversity in forests could increase due to climate change
17.11.2017 | Deutsches Zentrum für integrative Biodiversitätsforschung (iDiv) Halle-Jena-Leipzig
Win-win strategies for climate and food security
02.10.2017 | International Institute for Applied Systems Analysis (IIASA)
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses