The story of cancer care seems so simple: find the mutated gene that causes cancer and turn it off or fix it. But rarely does a single gene cause cancer.
More often, many genes are altered together to drive the disease. So the challenge becomes sorting out which altered genes are the most to blame in which cancers. A collaborative study between researchers at the University of Colorado Cancer Center and the National Cancer Institute (NCI) published today in the journal Clinical Cancer Research takes an important step toward answering this question in bladder cancer.
Dan Theodorescu, M.D., Ph.D., director of the University of Colorado Cancer Center, and colleagues from the National Cancer Institute show genes commonly mutated in bladder cancer, implying at least two distinct genotypes and phenotypes for the disease.
Credit: CU Cancer Center
Specifically, the study examined a mutation-rich layer of the genome called the exome of 54 bladder tumors from primarily Caucasian patients. The study is the first to show alterations in the gene BAP1 in 15 percent of tumors; the gene is a likely tumor suppressor and so bladder cancers with alterations in this gene may be without an important check on the growth and survival of bladder cancer tissue.
Somatic BAP1 alterations contribute to a high frequency of tumors (10/14, 71 percent) with defects in genes encoding BRCA1 and BRCA2 pathway proteins, pathways that have been previously implicated in breast and other cancer types.
More surprising, a second, highly independent genetic pathway was found in 69 percent of 54 tumors, in which alterations of the TERT promoter created what is effectively a second subset of bladder cancer. The TERT promoter mutations did not significantly correlate with somatic alterations in other cancer genes, indicating that this alteration confers a presumed oncogenic benefit independent of other cancer gene alterations.
The gene KDM6A was frequently altered in 24 percent of tumors, and the study shows that experimental depletion in of KDM6A in human bladder cancer cells enhanced in vitro proliferation, in vivo tumor growth, and cell migration, confirming its role as a cancer driver and tumor suppressor in bladder tissue.
The study revealed other surprising relationships between the types of genetic alterations in bladder tumors. BAP1 somatic mutations may correlate with papillary features in some bladder tumors and were significantly more frequent in Caucasian patients than Chinese patients, indicating ethnicity, lifestyle, or exposure may influence somatic BAP1 mutations.
BAP1 and KDM6A mutations significantly co-occurred in tumors, indicating they likely supply mutually reinforcing survival advantages to cancer cells. Finally, just four genes encoding chromatin remodeling enzymes, BAP1, KDM6A, ARID1A, and STAG2, were altered in 46 percent of 54 tumors and demonstrate a major contribution from somatic alterations targeting chromatin remodeling functions in bladder cancer.
"Taken together, we have identified new subtypes of bladder cancer that are related by somatic and germline genetic alterations that are observed in patient tumors. These subtypes may be vulnerable to subtype-specific therapeutic targeting. For example, many tumors in this study possessed cells with mutations targeting the BRCA DNA repair pathway indicating they are likely to be deficient in their ability to repair DNA," says Dan Theodorescu, MD, PhD, professor of Urology and Pharmacology, director of the University of Colorado Cancer Center and the paper's senior author.
"Thus the tumor cells should be especially sensitive to chemotherapeutic drugs that create DNA damage. This is an excellent example of a case in which basic science can now suggest targeted treatments that have the real possibility to benefit patients," says Michael Nickerson PhD, staff scientist and lead author from the National Cancer Institute.
Located on the Anschutz Medical Campus, the University of Colorado Cancer Center is Colorado's only National Cancer Institute-designated comprehensive cancer center, a distinction recognizing its outstanding contributions to research, clinical trials, prevention and cancer control. CU Cancer Center is a member of the prestigious National Comprehensive Cancer Network®, an alliance of the nation's leading cancer centers working to establish and deliver guidelines for clinical cancer practice. Our primary clinical care partner, the University of Colorado Hospital, was recently ranked #15 for cancer care by U.S. News & World Report. CU Cancer Center is comprised of more than 350 researchers and physicians at three state universities and other institutions, all working toward one goal: Translating cancer science into life. For more information visit Coloradocancercenter.org and follow CU Cancer Center on Facebook and Twitter.
Garth Sundem | Eurek Alert!
Purdue cancer identity technology makes it easier to find a tumor's 'address'
16.11.2018 | Purdue University
Microgel powder fights infection and helps wounds heal
14.11.2018 | Michigan Technological University
Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.
Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...
Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.
Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...
Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.
In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...
On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.
When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure
Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...
09.11.2018 | Event News
06.11.2018 | Event News
23.10.2018 | Event News
16.11.2018 | Health and Medicine
16.11.2018 | Life Sciences
16.11.2018 | Life Sciences