An analysis of genetic mutations in urothelial carcinoma of the bladder has identified potential therapeutic targets for treating the disease, for which no new treatments have been approved in 30 years.
Standard treatment for the most common type of bladder cancer, urothelial carcinoma of the bladder, includes surgery and cisplatin-based chemotherapy—and hasn't changed in decades. No targeted therapies have been approved for the disease, which kills an estimated 150,000 people worldwide every year.
To help improve the treatment outlook, investigators in The Cancer Genome Atlas (TCGA) Research Network used whole-exome sequencing to catalog mutations in 131 urothelial bladder tumors, collected at 19 research sites in North America. The cancers had grown into the cells lining the organ and invaded the muscle layer of the bladder.
The study, published recently in Nature, identified therapeutic targets that may respond to FDA-approved targeted drugs in 69% of the tumors. Those included mutations in the PI3K/AKT/mTOR pathway, found in 42% of the tumors. Mutations in TP53 were identified in 49% of the tumors. TP53 mutations have been associated with many types of cancer, including breast, colorectal, and some brain cancers, but these mutations are not targetable.
In total, the researchers identified statistically significant recurrent mutations in 32 genes in urothelial bladder cancer, including nine never before associated with the disease. One of those nine, MLL2, a chromatin-modifying enzyme, was identified in 27% of the tumors; MLL2 mutations have previously been identified in some childhood brain cancers and lymphomas. The other eight genes occurred in 2% to 20% of the tumors. The identified mutated genes have biologically important roles in cell-cycle regulation, chromatin regulation, and kinase signaling pathways.
John Weinstein, MD, PhD, of The University of Texas MD Anderson Cancer Center, led the project with Seth Lerner, MD, of Baylor College of Medicine, both in Houston. Weinstein notes that large-scale genomic studies are increasingly motivating researchers to group tumors by their molecular profiles as well as their tissue of origin. Weinstein says the two organizational structures—by tissue and by gene—are “complementary.”
For diseases like muscle-invasive urothelial bladder cancer, identifying mutations that are targeted by therapies for other cancers points to new indications for an existing drug. “Understanding one type of cancer may help us understand others in terms of targets for therapy,” he says. “The aggregation of the TCGA projects has implications for patients and their families, who are suffering from all of the cancer types we're trying to understand.”
Weinstein calls the study a snapshot in time, noting that data from additional tumors will provide researchers with an even more accurate view of the genetic landscape of bladder cancer. Since the authors completed their analysis, the TCGA tissue sample bank has more than tripled in size—to more than 400 muscle-invasive urothelial tumors. Weinstein says the researchers recently launched an integrated analysis on the larger tissue set.
“The data keep coming, and the understanding keeps coming,” he says.