Gene set breaks high-grade bladder cancer into two subtypes

Chapel Hill, NC-Researchers at the University of North Carolina School of Medicine, Chapel Hill have identified a discrete set of genes that segregate high-grade bladder cancer into two distinct subtypes-basal-like and luminal-each of which appears to have its own molecular characteristics and outcome. The authors also found that the two subtypes share many of the characteristics seen in basal and luminal breast cancer subtypes, a discovery with clinical implications.

The finding allowed the creation of a predictor, a set of 47 genes (bladder cancer analysis of subtypes by gene expression, or BASE47), which is now undergoing continuing clinical study to clarify its diagnostic and prognostic utility. The outcomes of these studies may serve to influence therapeutic design and decisions. Establishing the prognostic value of BASE47 would seem to allow therapeutic decisions to be refined to meet the character of the cancer. The subtypes identified by the genetic assay cannot otherwise be identified by standard histopathology.

An early assessment of the prognostic value of BASE47, conducted in conjunction with its creation, found that the basal-like bladder tumors identified by the screen had a significantly decreased disease-specific (p=.0194) and overall survival (p=.0081).

Senior author William Y. Kim, MD, told Urology Times there were three take-home messages to be derived from the study, which was published in the Proceedings of the National Academy of Sciences (2014; 111:3110-5).

Dr. Kim"The first is that cancers have similarities at the RNA expression level. There are likely more similarities than we have initially appreciated. The second is that we have simplified some of the heterogeneity of high-grade tumors and can separate them into groups. Currently, this cannot be done pathologically. The third take-home is that the basal-like subtype has a worse prognosis than the luminal-like subtype," said Dr. Kim, associate professor of medicine and genetics at the University of North Carolina.

To create BASE47, Dr. Kim and his colleagues merged selected data from four publicly available urothelial carcinoma data sets to create a metadata set of the genes involved in 262 high-grade, muscle-invasive bladder cancers. Analysis of these genes resolved to a 47-gene signature that reliably differentiated high-grade muscle-invasive bladder tumors into "basal-like" and "luminal" cancer. The signature was verified by a second data set of genes from the Memorial Sloan Kettering Cancer Center, New York.

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Gene set could help with treatment decisions

Dr. Kim said one of the motivations for the study was the observation that high-grade bladder tumors are unpredictable.

"High-grade bladder tumors as a whole present with extremely heterogeneous outcomes even though, from a pathological standpoint, they all look the same. There is no way, up to this point, of telling which patients would do worse and which might do better. Being able to do so would be important for two reasons: The median age at diagnosis is early 70s, and many of the patients have comorbid diseases such as COPD or heart disease, perhaps because smoking is a risk factor for both the cancer and many other diseases,” Dr. Kim said.

“Although we have somewhat effective chemotherapy for bladder cancer, the actual delivery of chemotherapy presents a challenge to patients who have compromised health. The BASE47 may help with treatment decisions," he added.

Finding genetic similarities between the bladder and breast cancer subtypes may have clinical implications because it is established that basal-like tumors in breast cancer are more responsive to chemotherapies. It is possible that this sensitivity to specific therapies may be found in cancers with similar genetic features.

"I think this study is going down two avenues. The first would be to further validate the prognostic value of BASE47, and the second is to determine the response of the subtypes to current and investigative therapies," Dr. Kim said.

He noted that the genes in the study were derived from frozen tumor samples, which are not routinely clinically collected. He and his colleagues are working to create an assay that could be applied to paraffin-embedded samples. Doing so would make the assay more efficient and cost effective.

Dr. Kim is an inventor on the patent for BASE47.UT

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