TCGA shines light on bladder cancer

Bladder cancer is revealed to resemble certain subtypes of breast, lung and head and neck cancers, including mutations in similar pathways

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BETHESDA, Md.—The Cancer Genome Atlas (TCGA), a joint collaboration by the National Cancer Institute (NCI) and the National Human Genome Research Institute of the National Institutes of Health, has been releasing in-depth characterizations of different cancer types for several years, publishing data on common mutations and possible therapeutic targets in an effort to aid cancer research and treatment development. In the most recent analysis, TCGA investigators looked at bladder cancer, specifically the type that invades the muscles of the bladder. This is the deadliest form of the disease, and there are no approved targeted treatments; the current standard of care consists of surgery and radiation together with chemotherapy. No secondary treatment options exist.
The study, “Comprehensive molecular characterization of urothelial bladder carcinoma,” was published online in Nature on January 29, 2014.
According to the NCI, “Most bladder cancers are transitional cell carcinomas (cancer that begins in cells that normally make up the inner lining of the bladder),” with additional types including squamous cell carcinoma and adenocarcinoma. Approximately 15,120 deaths were expected as a result of bladder cancer in the United States in 2013. Bladder cancer is expected to be the cause of more than 15,000 deaths in the United States this year, with the Nature study noting that approximately 150,000 deaths worldwide are attributed to urothelial carcinoma of the bladder each year.
“The definitive molecular portrait of bladder cancer by the TCGA Network has uncovered a promising array of potential therapeutic targets that provides a blueprint for investigations into the activity of existing and novel therapeutic agents in this cancer,” Louis Staudt, M.D., Ph.D., director, NCI Center for Cancer Genomics, noted in a press release.
Investigators analyzed DNA, RNA and protein data from 131 patients with muscle-invasive bladder cancer who were treatment-naïve, and found recurrent mutations in 32 genes, nine of which had not been known previously to be mutated. Nearly half of the tumor samples presented with mutations in the TP53 gene, with mutations and other abnormalities discovered in the RTK/RAS pathway in 44 percent of the analyzed tumors. These two pathways deal with the regulation of cell division and cell growth and development, respectively. In addition, genes responsible for regulating chromatin were found to be mutated more frequently in bladder cancer than any other common cancer studied so far. Potential drug targets were identified in 69 percent of the studied tumors.
“This project has dramatically improved our understanding of the molecular basis of bladder cancers and their relationship to other cancer types,” commented lead author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center. “In the long run, the potential molecular targets identified may help us to personalize therapy based on the characteristics of each patient’s tumor.”
In addition to mutations witnessed in the RTK/RAS pathway, which is mutated in many types of cancer, frequent mutations were also found in the HER2 gene, which is commonly mutated in some types of breast cancer. Additional research moving forward will likely involve testing whether existing and developing breast cancer therapeutics have any utility in treating this subset of bladder cancer. Recurring mutations and fusions with other genes were discovered with FGFR3 and the PI3-kinase/AKT/mTOR pathway as well, which, like TP53 and the RTK/RAS pathway, also mediate cell division and growth.
“We’ve organized our medical care around the affected organ system,” said Seth Lerner, M.D., professor and chair in urologic oncology at Baylor College of Medicine in Houston and a senior author of the study. “We have thought of each of these cancers as having its own characteristics unique to the affected organ. Increasingly, we are finding that cancers cross those lines at the molecular level, where some individual cancers affecting different organs look very similar. As targeted drug agents go through preclinical and clinical development, we hope that rather than treating 10 percent of breast cancers or 5 percent of bladder cancers, it eventually will make sense to treat multiple cancer types where the target is expressed.”
This cancer type shares a similarity with lung and head and neck cancers as well, in that smokers are at higher risk of developing bladder cancer. More than 70 percent of the cases studied in this latest TCGA analysis were seen in current or former smokers. A 2011 study from the NCI, which looked at data from over 450,000 individuals, found that smoking was responsible for roughly half of female bladder cancer cases, “similar to the proportion found in men in current and previous studies.”
The TCGA Research Network has so far published analyses on a variety of cancers, including glioblastoma multiforme, ovarian serous adenocarcinoma, colorectal adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, endometrial cancer, acute myeloid leukemia and kidney (clear cell renal cell carcinoma) cancer.

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