Bladder Cancer Genome Analysis Reveals Novel Targetable Mutations

A new analysis of the exome of primary bladder cancer has found a relatively frequent mutation in a gene called BAP1 (BRCA1 associated protein-1). Mutations in this gene were found in 15% of tumors and were linked to alterations in the BRCA pathway, including mutations in the BRCA1 or BRCA2 genes. This is the first study, according to the authors, to identify BAP1 mutations in bladder cancer.

Those bladder cancer patients harboring a BAP1 mutation may be susceptible to treatment with PARP inhibitors combined with DNA-damaging agents, according to the study authors.

The mutations in BAP1 correlated with papillary features in a fraction of the bladder tumors analyzed, and were more prevalent among Caucasian patients than in Chinese patients analyzed-only 1% of the 99 Chinese patient tumors harbored a mutation in the gene (P=.003). According to the authors, lifestyle, exposure, or ethnicity could influence these somatic BAP1 mutations.

BAP1 is likely a tumor suppressor gene, that when altered results in unchecked growth and survival of bladder cancer cells. Mutations in this gene have been previously identified in kidney cancer, melanoma, and mesothelioma.

BAP1 mutations frequently occurred along with KDM6A (histone lysine (K)-specific demethylase 6A) mutations suggesting that these two mutations may, in concert, promote survival and proliferation of bladder cancer cells. KDM6A was found to be mutated in 24% of the tumors analyzed.

Both BAP1 and KDM6A encode chromatin-remodeling proteins. The analysis found that four genes for these chromatin-remodeling proteins were altered in 46% of the bladder tumors analyzed.

Prior published studies using next generation sequencing to analyze bladder cancer came from tumor samples of Chinese patients. In the current study, Dan Theodorescu, MD, PhD, professor of urology and pharmacology, director of the University of Colorado Cancer Center, and colleagues analyzed samples of bladder tumors from 54 patients in the United States using whole exome and targeted sequencing as different ethnicities may have differences in the bladder tumor mutation landscape.

Bladder cancer is the fifth most common cancer in the world, with about 386,000 cases and 150,000 deaths reported in 2008. Thus far, research into bladder cancer and targeted therapies have lagged behind research and drug development for other types of tumors such as breast and prostate.

The somatic mutations identified so far in low-grade and non-muscle invasive (NMI) bladder cancer--which accounts for about 80% of cases--includes overexpression of HRAS (Harvey rat sarcoma viral oncogene homolog), mutations in FGFR3 (fibroblast growth factor receptor 3), and in KDM6A. This type of bladder cancer can be frequently and successfully treated with surgery and immunotherapy. But the 20% of patients with muscle-invasive tumors have a 5-year survival rate of less than 50%. This tumor type has been found to harbor mutations in HER2, EGFR, TP53, and RB1. Bladder cancer is among those cancers that have the most accumulated somatic mutations. Further genomic analyses of bladder tumors are needed in order to identify potential targets for therapy.

The researchers also found mutational variants of the promoter of the telomerase gene, TERT, in 69% of the tumors, but that these were not significantly associated with mutations in BAP1 or other bladder cancer genes. Somatic TERT mutations have recently been identified in melanoma and glioma.

The study also identified three additional somatic mutations, in the CHD1, CHD1L, and GCN1L1 genes that may be relevant for the disease.

In functional assays in vitro and in vivo, depletion of the KDM6A gene boosted bladder cancer cell growth and cell migration. The status of the KDM6A gene may provide a prognostic marker for bladder cancer, according to the authors.

“We are now developing diagnostics based on these results to be able to detect bladder cancer non- invasively in urine and blood samples,” Theodorescu told OncoTherapy Network.