Researchers may have uncovered how urothelial carcinoma originates and progresses, according to a novel study published by Nguyen et al in Nature. The findings provided insights into the biology of urothelial carcinoma and may point to new therapeutic strategies for this difficult-to-treat cancer type.
Background
Urothelial carcinoma—occurring in about 80,000 patients per year in the United States—originates from cells that line the bladder, urethra, and tubes that drain urine from the kidneys. Although the disease can be cured with surgery if caught early, about 30% of cases are diagnosed at later stages, when it is more challenging to treat successfully.
Study Methods and Results
In the study, the researchers examined malignant and premalignant urothelial cells taken from the same set of patients at different disease stages. They used whole-genome sequencing and advanced computational methods to map common DNA mutations, complex structural variants, and their timing.
The researchers found that APOBEC3 enzymes may cause early mutations that may help trigger the development of this urothelial carcinoma. They noted the enzymes evolved to disable infecting retroviruses by editing their viral DNA; however, it is known that they can sometimes mutate cells’ own DNA.
“The exact role of APOBEC3-induced mutations in cancer initiation hasn’t been clear,” stressed co–senior study author Bishoy Faltas, MD, Associate Professor of Medicine and of Cell and Developmental Biology and the Gellert Family–John P. Leonard MD Research Scholar in Hematology and Medical Oncology at Weill Cornell Medicine, Chief Research Officer at the Englander Institute for Precision Medicine, an oncologist at the NewYork–Presbyterian/Weill Cornell Medical Center, and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “[Nonetheless], we found that these mutations appear early in urothelial [carcinoma], occurring even in premalignant urothelial tissue.”
The researchers discovered that cisplatin and other platinum-based chemotherapies were capable of causing further prominent bursts of mutations, some of which may allow urothelial carcinoma cells to survive better and spread, regardless of treatment. In addition, urothelial carcinomas were found to contain complex rearrangements of their DNA that gave rise to circular segments of DNA. These extrachromosomal DNAs existed apart from chromosomes in the cell nucleus and could sometimes harbor hundreds of copies of cancer-driving growth genes. The researchers revealed that these extrachromosomal DNA events persisted and became more complex, incorporating new DNA segments after treatment, suggesting they contributed to therapeutic resistance.
As a result of their findings, the researchers experimentally modeled an extrachromosomal DNA version of one of these genes, called CCND1—a master regulator of the cell cycle in the laboratory. They confirmed that the gene in this extrachromosomal configuration drove treatment resistance.
Conclusions
“Our findings define new fundamental mechanisms driving [urothelial carcinoma] evolution—mechanisms that we can now think about targeting with therapies,” highlighted Dr. Faltas.
The researchers hope their research can illuminate the factors that trigger and drive urothelial carcinoma. “Traditionally, when analyzing tumor genomes, we’ve used methods that analyze only a tiny fraction of their DNA, but we’ve come to realize that there’s a lot more to discover if we sequence all their DNA and use smart methods to evaluate that data,” explained co–senior study author Olivier Elemento, PhD, Professor of Physiology and Biophysics at Weill Cornell Medicine and Director of the Englander Institute for Precision Medicine. “This collaboration vindicates that strategy,” he added.
The researchers are currently planning to conduct larger collaborative studies to better understand urothelial carcinoma biology by using whole-genome sequencing of DNA along with readouts of gene activity not just in bulk tumor samples but in individual tumor cells. They expect to further explore potential clinical applications of their research and are hopeful that a new U.S. Food and Drug Administration–approved drug targeting the ERBB2 gene product—the HER2 receptor protein also found on breast tumor cells—could be effective in patients with urothelial carcinoma with strong signs of ERBB2 extrachromosomal DNAs. Additionally, the researchers noted they are investigating strategies to block extrachromosomal DNA formation and maintenance.
“Combining … two sets of information at the single-cell level would be tremendously important and interesting,” concluded co–senior study author Nicolas Robine, PhD, Director of Computational Biology at the New York Genome Center.
Disclosure: The research in this study was supported in part by the National Cancer Institute and the National Center for Advancing Translational Science, both part of the National Institutes of Health; the U.S. Department of Defense; the Starr Cancer Consortium; the Leo & Anne Albert Institute for Bladder Cancer Care and Research; the Translational Research Program in the Department of Pathology and Laboratory Medicine at Weill Cornell Medicine; and the New York Genome Center’s Polyethnic-1000 Initiative. For full disclosures of the study authors, visit nature.com.
