The researchers observed somatic STAG2 alterations in 17% of tumors and these alterations were associated with a poor prognosis.
The findings suggest that STAG2 alterations may be a marker for an especially aggressive form of the disease. The STAG2 and KDM6A genes are located on the X chromosome, which may explain why men with only one copy of these cancer genes are more likely to develop bladder cancer, according to the researchers.
Dr. Theodorescu said these new findings help provide a more complete picture of the genetic landscape of bladder cancer.
He said now it may be easier to pick apart the biology of how these alterations cause cancer and how to intervene to better manage or stop the disease. It is possible that PARP inhibitors now on the market may be of use to a significant number of bladder cancer patients.
“These drugs are out there. These have been FDA-approved for other indications and if we have a successful phase II trial, then they could start using it off label. It is conceivable in 24 months we could have phase II results. That would be reasonable to know if we are getting some effect,” Dr. Theodorescu told Cancer Therapy Advisor.
“I don’t want to give people false hope with unrealistic timelines. You have delays and this and that, but 24 months is not unreasonable.”
The TERT gene encodes the enzyme telomerase and the concentration of telomerase helps to determine the length of telomeres, which are the protective genetic material attached to the ends of chromosomes.
The alterations so frequently seen in these samples of bladder cancer were in regions of DNA just upstream from the TERT gene (“promoter” regions).
New data show that TERT alterations lead to shorter telomere length in human samples of bladder tumor tissue when compared with telomere length in surrounding healthy tissue from the same patient.
A meta-analysis conducted in 2011 analyzed telomere length and cancer and it showed that shorter telomeres are associated with the development of many types of cancer.
Gopal Gupta, MD, who is an assistant professor of urology at Loyola University Health System in Chicago, IL, said these new findings by Dr. Theodorescu and colleagues are interesting and that their study suggests an entire new way to risk stratify bladder cancer.
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“We have only started to understand the genetics of bladder cancer, and epigenetics is another readout that may help risk stratify bladder cancer. Telomerase-related genes are very interesting and have been used as prognostics in several different cancers, and now we have some insight into their role in bladder cancer. I don’t think we can reach any conclusions about targeted therapy based on these findings, but certainly it is helpful in understanding genetic mutations in bladder cancer,” Dr. Gupta told Cancer Therapy Advisor.