Study reveals DNA mutations and structures that cause bladder cancer

How bladder cancer begins and progresses has been shed light like never before in a study led by researchers at Weill Cornell Medicine and the New York Genome Center. Researchers have discovered that antiviral enzymes that mutate the DNA of normal and cancer cells are key promoters of the early development of bladder cancer, and that standard chemotherapy is also a potent source of mutations.

Researchers also found that overactive genes within abnormal circular DNA structures in tumor cell genes lead to bladder cancer’s resistance to treatment. These findings provide new insights into the biology of bladder cancer and point to new therapeutic strategies for this difficult-to-treat cancer.

The study, published September 9 in Naturefocused on the main form of bladder cancer, urothelial carcinoma, which arises from the cells that line the bladder, urethra, and tubes that drain urine from the kidneys. The researchers examined malignant and pre-cancerous urothelial cells taken from the same group of patients at different stages of the disease. They used whole genome sequencing and advanced computational methods to map common DNA mutations, complex structural variants and their timing.

“Our findings define new fundamental mechanisms driving bladder cancer progression – mechanisms that we can now consider targeting with therapies,” said co-senior author Dr. Bishoy Faltas, a researcher of the Gellert-John P. Leonard MD family in hematology and medical oncology. and associate professor of medicine and cellular and developmental biology at Weill Cornell Medicine, and oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Dr. Nicolas Robine, director of computational biology at the New York Genome Center, and Dr. Olivier Elemento, director of the Englander Institute for Precision Medicine and professor of physiology and biophysics at Weill Cornell Medicine, also led the study with Dr. Faltas. . Co-first authors were Duy Nguyen, a technician in the Faltas lab (now a doctoral student at Harvard Medical School); William Hooper, bioinformatics researcher at the New York Genome Center; and Dr. Weisi Liu, instructor at the Faltas Lab.

Major therapeutic targets are being concentrated

Bladder cancer occurs at a rate of approximately 80,000 cases per year in the United States. It can be cured with surgery if caught early, but around 30 percent of cases are diagnosed at later stages, when it is much more difficult to treat successfully.

Researchers in the new study found strong evidence that APOBEC3 enzymes cause early mutations that could help trigger the development of this type of cancer. These enzymes have evolved to deactivate infectious retroviruses by modifying their viral DNA, although they are known to sometimes mutate the DNA of cells.

“The exact role of APOBEC3-induced mutations in cancer initiation is unclear,” said Dr. Faltas, who is also director of research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “But we found that these mutations appear early in urothelial cancer, occurring even in pre-cancerous urothelial tissue.”

In his laboratory, Dr. Faltas focuses on studying the role of these mutagenic enzymes in the development of cancer.

Researchers have found that cisplatin and other platinum-based chemotherapies cause further bursts of significant mutations, some of which likely allow urothelial cancer cells to better survive and spread despite treatment.

A third major finding is that urothelial tumors often contain complex rearrangements of their DNA that give rise to circular segments of DNA. These “extra-chromosomal DNA” (ecDNA) exist independently of the chromosomes in the cell nucleus and can sometimes harbor hundreds of copies of cancer-causing growth genes. Researchers found that these ecDNA events persist and become more complex, incorporating new DNA segments after treatment, suggesting that they lead to treatment resistance.

This prompted the team to experimentally model an ecDNA version of one of these genes, called CCND1, a master regulator of the cell cycle in the laboratory. The results of these experiments confirmed that CCND1 in this extrachromosomal configuration drives treatment resistance.

Overall, the results paint a much clearer picture of the factors that trigger and drive urothelial cancer.

“Traditionally, when analyzing tumor genomes, we have used methods that analyze only a tiny fraction of their DNA, but we realized there was much more to discover if we sequenced all of their DNA and “We’re using intelligent methods to evaluate it,” said Dr. Elemento. “I think this collaboration justifies this strategy.”

Researchers at the Englander Institute and New York Genome Center plan future, larger collaborative studies to delve even further into the biology of urothelial cancer, such as by performing whole-genome DNA sequencing as well as reading the gene activity, not only in bulk tumor samples, but in individual tumors. cells.

“Combining these two sets of information at the single-cell level would be extremely important and interesting,” Dr Robine said.

The researchers also plan to study potential clinical applications of this work. Investigators hope that a new FDA-approved drug targeting the ERBB2 gene product – the HER2 receptor protein, also found on breast tumor cells – will work particularly well in urothelial cancer patients with strong signs of ERBB2 cDNA. They are also working to find ways to block the formation and maintenance of ecDNA.