The Cancer Genome Atlas: Bladder Cancer

The Cancer Genome Atlas (TCGA) project now includes a recently reported comprehensive molecular characterization of muscle-invasive urothelial bladder carcinoma (presented January 31, 2014, at the Genitourinary Cancers Symposium and published simultaneously online in Nature).^1,2

The hope is that these genetic discoveries will translate to identification and development of new treatments for bladder cancer. New therapies for bladder cancer represent an unmet need. Over the past decade, kidney and prostate cancer therapy has seen an explosion of novel agents, but no new treatment for bladder cancer has been identified since the 1970s.

The TCGA findings on muscle-invasive urothelial bladder cancer were presented by Jonathan Rosenberg, MD, Section Chief of the Non-Prostate Program in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.

The 2 major take-home messages of his presentation were:

• The majority of patients with muscle-invasive urothelial bladder carcinoma have actionable mutations that can be targeted in selected populations with either drugs approved by the US Food and Drug Administration or investigational agents.
• Epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting that there may be a different paradigm for therapeutic intervention. Seventy-six percent of tumors had 1 inactivating epigenetic mutation and 41% had 2. More clinical and laboratory research is needed with drugs that target these alterations, such as histone deacetylase inhibitors, DNA methyltransferase inhibitors, and bromodomain inhibitors. These drugs may be useful in subsets of patients, Rosenberg said.

Rosenberg and colleagues analyzed DNA from 131 muscle-invasive urothelial bladder cancer tumors and corresponding normal samples (predominantly blood). They determined that bladder cancer was one of the most highly mutated tumor types, with each tumor possessing an average of 302 exonic mutations, 204 segmental alterations in DNA copy number, and 22 large-scale genomic alterations. Thirty-two recurrent significantly mutated genes were identified that appear to be involved in bladder cancer pathogenesis. Some of these genetic abnormalities had not been previously reported in bladder cancer or in other cancers included in the TCGA, he said.

Three clusters of abnormalities were identified based on an integrated analysis of both mutations and copy number: a genomic amplification cluster; a p16-deleted cluster; and a p53-mutated cluster.

“These clusters suggest that there may be different oncogenic mechanisms involved in the development of muscle- invasive bladder cancer, but we don’t know yet whether any of them are clinically relevant,” Rosenberg commented.

Between mutation and copy number analysis, potential targets were identified in 69% of the tumors, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets in the RTK/MAPK pathway (including ERBB2).

Rosenberg said that this work represents progress in bladder cancer, and carefully designed trials are needed to test therapies directed to these potentially actionable genetic aberrations.

References
1. Rosenberg JE, Kim J, Cherniack A, et al. Somatic genomic alterations in urothelial cancer: results of the Cancer Genome Atlas (TCGA) bladder cancer (BC) analysis. J Clin Oncol. 2014;32(suppl 4). Abstract 285. Presented at: 2014 Genitourinary Cancers Symposium; January 31, 2014; San Francisco, CA.
2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315-322.