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!
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Information Technology
17.07.2018 | Materials Sciences
17.07.2018 | Power and Electrical Engineering