Recent research has provided unprecedented insights into the origins and progression of bladder cancer. A study conducted by researchers at Weill Cornell Medicine and the New York Genome Center revealed that specific antiviral enzymes, which alter the DNA of both normal and cancerous cells, play a significant role in the early stages of bladder cancer. Additionally, conventional chemotherapy has also been found to be a substantial source of mutations. Furthermore, the study identified that hyperactive genes within unusual circular DNA formations in tumor cells contribute to the resistance of bladder cancer to treatment. These discoveries offer new perspectives on the biology of bladder cancer and suggest potential therapeutic approaches for this challenging disease.
The findings, published on September 9 in Nature, center on urothelial carcinoma, the primary form of bladder cancer, which arises from the cells that line the bladder, urethra, and urinary tract. The team analyzed cancerous and pre-cancerous urothelial cells from patients at various stages of the disease. By utilizing whole-genome sequencing alongside advanced computational techniques, they mapped common DNA mutations and complex structural variations, following their progression over time.
“Our research unveils critical new mechanisms that drive the evolution of bladder cancer, which we can now consider targeting with therapies,” stated Dr. Bishoy Faltas, co-senior author of the study, who is a Gellert Family-John P. Leonard MD Research Scholar in Hematology and Medical Oncology at Weill Cornell Medicine and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Dr. Nicolas Robine, who is the director of computational biology at the New York Genome Center, and Dr. Olivier Elemento, director of the Englander Institute for Precision Medicine and professor at Weill Cornell Medicine, collaborated with Dr. Faltas on this study. The lead authors include Duy Nguyen, previously a technician in the Faltas Laboratory and now a doctoral student at Harvard Medical School; William Hooper, a bioinformatics scientist at the New York Genome Center; and Dr. Weisi Liu, an instructor in the Faltas Laboratory.
Key Areas for Treatment Targeting Identified
Bladder cancer affects approximately 80,000 individuals each year in the United States. If detected early, it can be treated successfully through surgery; however, around 30% of cases are diagnosed at more advanced stages, making effective treatment more challenging.
The study highlighted compelling evidence that the APOBEC3 enzymes are responsible for early mutations that may initiate the development of this type of cancer. These enzymes have evolved to target and disable retroviruses by editing their DNA, although they can also cause mutations in the DNA of healthy cells.
“The precise impact of APOBEC3-induced mutations in initiating cancer has not been entirely understood,” said Dr. Faltas, who is also the chief research officer at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “However, we have discovered that these mutations arise early in urothelial cancer, even in pre-malignant urothelial tissues.” Dr. Faltas’s research is currently focused on understanding how these mutagenic enzymes contribute to the evolution of cancer.
The researchers found that cisplatin and other platinum-based therapies lead to additional significant mutations, many of which seem to enhance the survival and spread of urothelial cancer cells despite treatment.
Moreover, a third important finding revealed that urothelial tumors frequently contain complex DNA rearrangements that create circular DNA segments. These “extra-chromosomal DNAs” (ecDNAs) exist separately from chromosomes within the cell nucleus and can hold numerous copies of genes that promote cancer growth. The team found that these ecDNA events continue and grow more complex after treatment, indicating their role in treatment resistance.
As part of their research, the team created a laboratory model of one such gene, CCND1, which is a key regulator of the cell cycle, in its extrachromosomal form. The experimental results confirmed that the CCND1 gene in this configuration contributes to resistance against treatment.
Overall, the research provides a clearer understanding of the factors that trigger and propel urothelial cancer.
“Historically, when we’ve analyzed tumor genomes, we focused on only a small portion of their DNA, but it has become evident that there is much more to uncover if we sequence all their DNA and employ sophisticated methods to analyze that data,” Dr. Elemento remarked. “This collaboration showcases the value of this approach.”
The researchers from the Englander Institute and the New York Genome Center are planning more extensive collaborative studies to delve deeper into urothelial cancer biology, including whole-genome sequencing of DNA along with gene activity assessments in individual tumor cells.
“Integrating these two sets of data at the single-cell level would yield incredibly important and intriguing insights,” added Dr. Robine.
The team also aims to explore potential clinical applications for their research. They are optimistic that a newly FDA-approved drug targeting the ERBB2 gene product—the HER2 receptor protein, also present in breast cancer cells—might be particularly effective for urothelial cancer patients exhibiting prominent signs of ERBB2 ecDNAs. Additionally, they are looking into methods to inhibit the formation and persistence of ecDNAs.
