Study reveals mutations and DNA structure that cause bladder cancer

A study led by researchers at Weill Cornell Medicine and the New York Genome Center sheds unprecedented light on how bladder cancer develops and progresses.

Researchers have found that an antiviral enzyme that mutates the DNA of normal and cancer cells is a key driver of early bladder cancer development, and that standard chemotherapy is a potent driver of mutations. . Researchers also discovered that an overactive gene within an abnormal circular DNA structure of a tumor cell gene causes bladder cancer to be resistant to treatment.

These findings provide new insights into the biology of bladder cancer and suggest new therapeutic strategies for this difficult-to-treat cancer.

the study, Published in Nature on October 9thfocused on urothelial carcinoma, the main form of bladder cancer. Urothelial cancer originates from the cells that line the tubes that drain urine from the bladder, urethra, and kidneys. The researchers examined malignant and pre-malignant urothelial cells from the same group of patients at different stages of the disease. They used whole-genome sequencing and advanced computational techniques to map common DNA mutations, complex structural variations, and their timing.

“Our findings reveal a new fundamental mechanism that promotes bladder cancer progression, a mechanism that can now be considered for targeting with therapeutics.” the author states. Dr. Bishoy FaltasJohn P. Leonard, M.D., of the Gellert family, is a researcher in hematology and medical oncology and an associate professor of medicine and cell and developmental biology at Weill Cornell Medical College and NewYork-Presbyterian/Weill Cornell Medical College. He is also the center's oncologist.

nicholas robindirector of computational biology at the New York Genome Center, and Olivier ElementHe, director of the Englander Institute for Precision Medicine and professor of physiology and biophysics at Weill Cornell Medical College, also led the study with Faltas. The co-first author was Duy Nguyen, a former Faltus Institute engineer (currently a doctoral student at Harvard Medical School). William Hooper, bioinformatics scientist at the New York Genome Center; Weisi Liu, instructor in the Faltas lab;

Approximately 80,000 cases of bladder cancer occur annually in the United States. Although it can be cured with surgery if detected early, approximately 30% of cases are diagnosed at a later stage, making successful treatment much more difficult.

Researchers in a new study found strong evidence that the APOBEC3 enzyme causes early mutations that may trigger the development of this type of cancer. These enzymes evolved to disable retrovirus infection by editing viral DNA, but they are known to sometimes mutate a cell's own DNA.

“It is not clear exactly what role mutations caused by APOBEC3 play in cancer development,” said Faltas, who is also the institute's principal investigator. Englander Precision Medicine Institute He is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College. “However, we found that these mutations appear early in urothelial cancer and also occur in precancerous urothelial tissue.”

In his lab, Dr. Faltas focuses on studying the role of these mutagenic enzymes in driving cancer evolution.

Researchers found that cisplatin and other platinum-based chemotherapy induce more prominent mutations, some of which may increase the survival rate of urothelial cancer cells and allow them to metastasize despite treatment. I discovered that.

The third major finding was that urothelial tumors often contain complex rearrangements of DNA that give rise to circular segments of DNA. These “extrachromosomal DNAs” (ecDNAs) reside separate from the chromosomes in the cell nucleus and can carry hundreds of copies of the proliferative genes that drive cancer. Researchers found that these ecDNA events persist and become more complex after treatment, incorporating new DNA segments, suggesting that these events are promoting resistance to treatment. .

This led the team to ly model an ecDNA version of one of these genes, CCND1., Master regulator of the cell cycle in the laboratory. The results of these experiments confirmed that this extrachromosomal configuration of CCND1 promotes treatment resistance.

Taken together, this finding paints a clearer picture of the factors that cause and drive urothelial cancer.

“Traditionally, when analyzing tumor genomes, we have used methods that analyze only a small portion of a tumor's DNA, but if we sequence all of the DNA and evaluate it in smart ways, we can discover much more. I realized I could do it with data,” Element said. “I think this collaboration supports that strategy.”

Researchers at the Englander Institute and the New York Genome Center are planning a large-scale collaboration in the future to delve deeper into the biology of urothelial cancer. For example, whole-genome sequencing of DNA with readouts of gene activity in individual tumors as well as bulk tumor samples. cell.

“If we could combine these two pieces of information at the single-cell level, it would be very important and interesting,” Robine said.

The researchers also plan to study potential clinical applications of this work. Researchers suggest that a new FDA-approved drug that targets the ERBB2 gene product, a HER2 receptor protein also present in breast cancer cells, may be particularly effective in patients with urothelial cancer who show strong signs of ERBB2 ecDNA. I hope so. They are also working on finding ways to block the formation and maintenance of ecDNA.

This research was supported by the National Cancer Institute and the National Center for the Advancement of Translational Sciences, part of the National Institutes of Health, and part of the U.S. Department of Defense. Starr Cancer Consortium, the Leo and Ann Albert Bladder Cancer Care and Research Institute, the Translational Research Program of the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College, and the New York Genome Center's Multi-Ethnic 1000 Initiative. Additional support was provided by.

Many of Weill Cornell Medicine's physicians and scientists maintain relationships and collaborate with outside organizations to foster scientific innovation and provide expert guidance. Institutions make these disclosures public to ensure transparency. Please see my profile for this information. Dr. Bishoy Faltas and Dr. Olivier Element.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.