Discovery 
November 30, 2017

DISCOVERY IN BLADDER CANCER

There probably won’t ever be just one wonder drug to help every person with advanced bladder cancer. That’s because – even if they have the same symptoms, same stage of cancer, and even the same course of disease – at the genetic level, they’re different. So if you have advanced bladder cancer and you’re sitting in a waiting room with several other people in the same boat, the drug that helps you might not help the guy sitting right beside you. But it probably will help some with your same subtype of cancer.

How do you know your subtype? From a tissue biopsy, ideally of metastatic cancer, which may have acquired different gene mutations from those seen in the primary tumor.

Scientists now know that there are 28 different genetic forms of prostate cancer, 11 different genetic forms of breast cancer, and at least five different genetic forms of bladder cancer. This is why, as we’ve discussed elsewhere in Discovery, the “one size fits all” approach to treating advanced cancer doesn’t work. It’s why scientists David McConkey, Ph.D., Director of the Johns Hopkins Greenberg Bladder Cancer Institute, and Woonyoung Choi, Ph.D., are working so hard toward precision diagnosis and treatment – starting with identifying the molecular subtypes of bladder cancer. They recently published their findings in European Urology.

“Because they are highly heterogeneous, bladder cancers are associated with unpredictable patterns of spread and responses to treatment,” McConkey explains, “but with next-generation DNA and RNA sequencing technology, we can actually see this heterogeneity at high resolution.” McConkey, Choi and others previously reported that bladder cancers can be grouped into RNA-based molecular subtypes that are “surprisingly similar” to the subtypes found in breast cancer. “What we did not know was whether the subtypes of bladder cancer were also associated with specific DNA mutation patterns – which could explain and predict someone’s sensitivity to conventional treatment, as well as gene-targeted drugs or immunotherapy.”

To address this question, McConkey and Choi led a collaborative project to characterize the DNA mutations and other DNA-based alterations in a large public data set. “Investigators from the University of North Carolina and Lund, Sweden, worked with us to assign the tumors to intrinsic molecular subtypes,” and then Choi characterized the DNA mutation patterns within them. The results confirmed that specific DNA mutation patterns indeed were associated with each subtype, and that these patterns could be used to increase the number of significant molecular subtypes beyond what was visible using RNA expression patterns alone.

“These results have immediate implications for using the molecular subtypes to guide our bladder cancer patients to precision treatment options,” says McConkey. “They also provide a new starting point for future laboratory studies aimed at identifying the specific genetic defects associated with these cancers.”