The Cancer Genome Atlas Project Explores Bladder Cancer

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Researchers have successfully completed a comprehensive molecular characterization of muscle-invasive urothelial bladder carcinoma as part of The Cancer Genome Atlas (TCGA) project. Results of the analysis were presented at the Genitourinary Cancers Symposium and published simultaneously online in Nature. Excitement about the discoveries was palpable, and the authors hope that this effort to characterize the bladder cancer genome will identify new therapies targeted to actionable mutations for clinical use in appropriately selected patients.

“We are not in our infancy, but you could say we are on the verge of adolescence [in this effort],� said lead investigator Jonathan E. Rosenberg, MD, section chief of the Non-Prostate Program in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.

Bladder cancer has been the “stepchild� regarding new drugs. There has been an explosion of new therapies for both prostate and renal cancer, while no new drugs for bladder cancer have been discovered since the 1970s. The hope is that the 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,� 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, he explained, which is second only to lung cancer and melanoma. Cigarette smoking did not correlate with the mutations identified.

Sifting through the wealth of data, 32 genes were identified that showed significant levels of recurrent somatic mutation. Some of the genes have been implicated in other cancers (eg, p53, PI3CA, ATM, and HER2), while several genes have not been identified previously in any cancer; these include CDKN1A, ERCC2, RXRA, ELF3, KLF5, and others.

Potential targets were identified in 69% of the tumors, including 42% with targets in the PIK3/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 both mutations and copy number: a genomic amplification cluster, a P16-deleted cluster, and a P53-mutated cluster. 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 key messages from this massive undertaking are as follows:

1. The majority of patients with muscle-invasive urothelial bladder carcinoma have actionable mutations that can be targeted with either FDA-approved drugs or 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. Seventy-six percent of tumors had 1 inactivating epigenetic mutation, and 41% had 2.

This research opens the door for opportunities to study both FDA-approved and experimental therapies that can target some of the abnormalities that have been identified. The trials must be carefully designed, Rosenberg said.

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