In the first whole-genome analysis conducted through the Roswell Park Cancer Institute (RPCI) Center for Personalized Medicine, researchers report that invasive bladder cancers demonstrate two distinct patterns of genetic alteration, one of which may result from defects in cells’ ability to replicate. The study, published online ahead of print in PNAS, the Proceedings of the National Academy of Sciences of the United States of America, is the second to employ whole-genome sequencing of bladder tumors, and lays the groundwork for development of personalized targeted therapies.
Genomic analysis of tumors from five patients with muscle-invasive transitional-cell carcinoma of the urinary bladder (TCC-UB), the least common but most serious form of bladder cancer, revealed two categories of tumors. Results showed profound genetic aberrations, including mutations of an important and widely studied tumor-suppressor gene, p53, in the first group of tumors, which were also characterized by chromosomal shattering, or chromothripsis. The researchers believe small rather than large fragments of DNA act as “stitchers” to repair the effects of chromothripsis, and postulate that a defective “replication-licensing complex” unites this class of tumors.
A second group of tumors demonstrated no evidence of chromothripsis, with fewer complex genomic changes, and a subset characterized by amplification of the GRIN2A gene, revealing a potential new target in bladder cancer therapeutics. While GRIN2A mutations have previously been associated with melanoma, the Roswell Park Cancer Institute study is the first to link this gene to bladder cancer.
“We knew before that bladder cancers are a particularly heterogeneous group, but now we’re starting to understand what causes these mutations and differences to occur and how we can potentially disrupt or exploit these processes for therapeutic benefit,” notes lead author Carl D. Morrison, MD, DVM, Executive Director of RPCI’s Center for Personalized Medicine and Director of the Division of Molecular Pathology. “The challenge is to develop a molecular taxonomy along the lines of what’s been accomplished in lung cancer, and these findings will advance that effort considerably.”
Approximately 73,000 American adults are newly diagnosed with bladder cancer each year. Roswell Park President and CEO Donald L. Trump, MD, FACP, a urologic oncologist and senior author on the paper, notes that the most dangerous form of bladder cancer is the type that invades the muscle wall of the bladder. Approximately 30 percent of bladder cancer is of this type; these tumors are usually first discovered when they are invasive. For 70 percent of patients with bladder cancer, meanwhile, tumors are first recognized when confined to the surface lining of the bladder. Some 20 percent of these “superficial” bladder cancers will progress to more dangerous muscle-invasive tumors.
“Given the limited range of options for treating muscle-invasive cancers currently, the need for better therapies is pressing,” says Dr. Trump. “We expect that these findings will, in the near future, help us to stratify patients with bladder cancer and direct them to appropriate therapies based on the molecular profile of their unique tumor, and may point the way to strategies for intervening to halt this continuum of disease progression.”
The authors also included collaborators from the Medical College of Wisconsin. The paper, “Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer,” is published in PNAS journal.
This study was supported in part by a grant from the National Cancer Institute (R01CA067267) and used shared resources supported by RPCI’s Cancer Center Support Grant from the NCI (P30CA016056).
Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma, Jared J. Gartner, Stephen C. J. Parker, Todd D. Prickett, Ken Dutton-Regester, Michael L. Stitzel, Jimmy C. Lin, Sean Davis, Vijaya L. Simhadri, Sujata Jha, Nobuko Katagiri, Valer Gotea, Jamie K. Teer, Xiaomu Wei, Mario A. Morken, Umesh K. Bhanot, NISC Comparative Sequencing Program, Guo Chen, Laura L. Elnitski, Michael A. Davies, Jeffrey E. Gershenwald, Hannah Carter, Rachel Karchin, William Robinson, Steven Robinson, Steven A. Rosenberg, Francis S. Collins, Giovanni Parmigiani, Anton A. Komar, Chava Kimchi-Sarfaty, Nicholas K. Hayward, Elliott H. Margulies, and Yardena Samuels, PNAS – doi: 10.1073/pnas.1304227110
Roswell Park Cancer Institute (RPCI)