Study uncovers molecular keys to invasive bladder cancer

The once sketchy landscape of the molecular defects behind bladder cancer now resembles a road map to new, targeted treatments thanks to the unified efforts of scientists and physicians at 40 institutions.

Deep molecular analysis of 131 muscle-invasive bladder cancer tumors found recurring defects in 32 genes for the cancer that currently has no targeted therapies. Findings by The Cancer Genome Atlas (TCGA) Research Network are published in the journal Nature. The TCGA is a joint project of the National Cancer Institute and the National Human Genome Research Institute of the National Institutes of Health.

“By dramatically increasing our knowledge of the molecular basis of bladder cancers, this project casts a spotlight on particular molecules and biological pathways that may serve as targets for a more individualized approach to therapy,” said project co-chair, lead and senior author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center in Houston.

“While many of these genomic alterations have been tied to other cancers, nine of these genes have never been reported as significantly mutated in any other type of malignancy,” Weinstein said. “These findings mark additional progress away from defining cancer by organ site and toward molecular classification that spans tumor types.”

Basis for investigating novel therapies and new uses of existing drugs

The most common bladder cancer, urothelial carcinoma, will kill an estimated 15,000 Americans in 2014, with 10 times as many deaths worldwide. Muscle-invasive disease is the most lethal form. Current treatment includes surgery, cisplatin-based multi-agent chemotherapy and radiation.

“These TCGA data provide a perfect storm for advancing treatment for muscle invasive and hard-to-treat cancer,” said project co-leader and co-senior author Seth P. Lerner, M.D., professor and chair of Urologic Oncology and Bladder Cancer program leader at Baylor College of Medicine in Houston.

“We found potential therapeutic targets in 69 percent of tumors and identified bladder cancer subtypes based on gene mutation and expression data,” Lerner said. “One subtype looks similar to squamous cell cancer of the head, neck and lung and basal-like breast cancer. Another subtype looks similar to luminal A breast cancer. These genomic similarities create a logical path to test targeted therapies from these other subtypes of cancer rather than treating bladder cancers as one disease.”

Lerner said long-term planning for clinical trials based on the TCGA data has begun in earnest and will continue this week during the 2014 Genitourinary Cancers Symposium in San Francisco.

Researchers analyzed tumors for genetic mutations, gene copy number (deletions and amplifications), gene expression of messenger RNA, microRNA and protein expression, among other factors.

Two biological pathways provided the most common therapeutic targets, including molecules addressed by drugs in clinical trials or approved for other types of cancer.
•45 percent of tumors had targets in the growth-factor-signaling receptor tyrosine kinase/MAPK pathway, including HER2 – best known as a drug target in about one third of breast cancers – in 15 percent of tumors, EGFR in 9 percent and FGFR3 in 17 percent.

•42 percent had targets in the PI3K/AKT/mTOR pathway, including PIK3CA, which occurred in 17 percent of tumors, TSC1 or TSC2 in 9 percent and AKT3 in 10 percent of tumors. PI3K inhibitors are under development and mTOR inhibitors have been approved for select cancers.

A striking new finding, Weinstein said, was of frequent alterations in genes involved with the regulation of chromatin, the combination of DNA and histone proteins that makes up chromosomes.

Chromatin remodeling greatly influences gene expression and the team found alterations in this pathway in 89 percent of tumors, more than in any other type of cancer analyzed to date. This makes bladder cancer a prime candidate for a new class of drugs under development, the authors noted.

Viral DNA was found in 6 percent of tumors, suggesting that viral infection might play a role in the development of a small percentage of bladder cancers.

More to come

“Bladder cancer investigators now have access to an enormous amount of data that they can dive into for hypothesis testing, validation and translational research,” Lerner said.

Over 700 tumor samples were received by Dec. 31, and all of those passing the rigorous quality control will be processed and analyzed, potentially tripling the sample size, Weinstein said.

David Kwiatowski, M.D., Ph.D., of Harvard Medical School and the Broad Institute of MIT and Harvard, is co-senior author of the paper. Other project leaders are data coordinator Chad Creighton, Ph.D., Baylor College of Medicine; analysis coordinators Rehan Akbani, Ph.D., MD Anderson, and Jaegil Kim, Ph.D., of the Broad Institute; manuscript coordinator: Margaret Morgan of Baylor College of Medicine. The writing team was Weinstein, Lerner, Kwiatowski, Creighton, Akbani, Xiaoping Su, Ph.D., and Michael Ryan, Ph.D., of MD Anderson; Peter Laird, Ph.D., of the University of Southern California, Raju Kucherlapati, Ph.D., of Harvard Medical School, and Katherine Hoadley, Ph.D., of the University of North Carolina Lineberger Cancer.

Additionally, clinical expertise was provided by Lerner, Kwiatowski, Jonathan Rosenberg, M.D., and Dean Bajorin, M.D., both of Memorial Sloan-Kettering Cancer Center in New York; Pathology review: Hikmat Al-Ahmadie, M.D., and Victor Reuter, M.D., of Memorial Sloan-Kettering, Bogdan Czerniak, M.D., Ph.D., MD Anderson, Donna Hansel, M.D., Ph.D., University of California, San Diego, and Brian Robinson, M.D., Weill Medical College of Cornell University; DNA methylation analysis: Laird and Toshinori Hinoue, Ph.D., University of Southern California; mRNA analysis: Hoadley, William Kim, M.D., and Jeffrey Damrauer of Lineberger Cancer Center at University of North Carolina, and Wei Zhang, Ph.D., Yuexin Liu, Ph.D., and Akbani of MD Anderson; miRNA analysis: Gordon Robertson, Ph.D., and Andrew Mungall, Ph.D., of Canada's Michael Smith Genome Sciences Center; transcript splicing analysis: Ryan and Weinstein; Protein analysis: Akbani and Gordon Mills, M.D., Ph.D., MD Anderson;. APOBEC: Dmitry Gordenin, Ph.D., of the U.S. National Institute of Environmental Health Sciences; Pathway/integrated analysis: Creighton, Nicholas Schultz, Ph.D., of Memorial Sloan-Kettering; and Evan Paull and Joshua Stuart, Ph.D., of the University of California, Santa Cruz; Chromosomal rearrangements and viral integration: Su of MD Anderson and Kucherlapati, Netty Santoso, Ph.D., Semin Lee, Ph.D., and Michal Parfenov, M.D., Ph.D., of Harvard Medical School. Batch effects: Akbani and Weinstein. Manuscript review: Richard Gibbs, Baylor College of Medicine, Chris Gunter, Ph.D., of Children's Healthcare of Atlanta and Matthew Meyerson, M.D., Ph.D., of the Broad Institute and Dana-Farber Cancer Institute, Boston.

Project coordinator is Margi Sheth of The Cancer Genome Atlas.

This work was funded by grants from NIH: U54HG003273, U54HG003067, U54HG003079, U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, and U24CA144025.