The Cancer Genome Atlas Project: Newly Discovered Molecular Alterations in Bladder Cancer May Lead to Novel Therapies

San Francisco, CA—Researchers have successfully completed a comprehensive characterization of molecular alterations in muscle-invasive urothelial bladder carcinoma as part of The Cancer Genome Atlas (TCGA) project. The results of the analysis were presented at the 2014 Genitourinary Cancers Symposium by Jonathan E. Rosenberg, MD, Section Chief, Non-Prostate Program, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, and published simultaneously online (The Cancer Genome Atlas Research Network. Nature. 2014 January 29 [Epub ahead of print]).

Excitement about the discoveries was palpable at the meeting, and the investigators hope that this effort to characterize the genomic features in bladder cancer will lead to the development of new therapies targeted to actionable mutations that could improve outcomes for appropriately selected patients.

“We are not in our infancy, but you could say we are on the verge of adolescence” in terms of this, said Dr Rosenberg. Bladder cancer has been the “stepchild” when it comes to the development of new drugs.

There has been an explosion of new therapies approved by the US Food and Drug Administration (FDA) for prostate cancer and for renal cancer, but no new drugs for bladder cancer have been discovered since the 1970s. The hope is that TCGA research will lead to filling this unmet need.
The TCGA Bladder Cancer Working Group successfully analyzed samples from 131 high-grade muscle-invasive urothelial carcinomas not previously treated with cytotoxic chemotherapy.

“Results paint an intricate picture of the multiple molecular players altered in this potentially lethal type of the disease, but they also bring to light promising actionable targets that may lead to more personalized therapeutic options beyond cisplatin-based chemotherapy,” Dr Rosenberg stated.
Analysis of the tumor tissue revealed multiple abnormalities with a high mutation rate. The research team found that each tumor, on average, featured 302 exon mutations, 204 alterations in DNA copy number, and 22 large-scale genomic arrangements. This represented 7.7 somatic mutations per megabase, Dr Rosenberg explained, which is second only to lung cancer and melanoma. Cigarette smoking did not correlate with the mutations identified.

Significant Genetic Alterations
Sifting through the wealth of data, 32 genes were identified that showed significant levels of recurrent mutation. Some of the genes have been implicated in other cancers, such as p53, PI3CA, ATM, and HER2, but several genes have not been identified previously in any cancer; these include CDKN1A, ERCC2, RXRA, ELF3, and KLF5, among others.

Potential targets were identified in 69% of the bladder cancer tumors, including 42% with targets in the PI3K/AKT/mTOR pathway, and 45% with targets in the RTK/MAPK pathway (including ERBB2).

Three clusters of abnormalities were identified based on an integrated analysis of mutations and copy number: a genomic amplification cluster, a P16-deleted cluster, and a p53-mutated cluster. Dr Rosenberg said that the clusters suggest that discrete oncogenic mechanisms may be implicated in the development of muscle-invasive bladder cancer, but it is not clear if this finding has clinical applicability.

The 2 key messages from this massive undertaking are:

  1. The majority of patients with muscle-invasive urothelialbladder carcinoma have actionable mutations that can be targeted with FDA-approved drugs or with investigational agents in appropriately selected populations
  2. Epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting another therapeutic approach with drugs that target these alterations

Of the tumors investigated, 76% had 1 inactivating epigenetic mutation, and 41% had 2.

This research opens the door for new opportunities to study FDA-approved drugs and investigational therapies that can target some of the molecular alterations that have been identified in this research. Clinical trials must be carefully designed for this purpose, Dr Rosenberg said.

Urothelial carcinoma of the bladder is associated with significant morbidity and an estimated 150,000 deaths annually worldwide.

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