NOV 12, 2024

How Genetic Mutations Promote Bladder Cancer Growth

WRITTEN BY: Carmen Leitch

There are about 80,000 new cases of bladder cancer every year in the US alone. About one-third of cases are diagnosed at late stages when the disease is hard to treat. Scientists have now learned more about how genetic mutations can increase the risk of bladder cancer and drive the progression of the disease. The findings have been reported in Nature.

Researchers have found that antiviral enzymes, which can mutate the genomes of both healthy and cancerous cells, are major promoters of bladder cancer in its early stages.

The most common form of bladder cancer is urothelial carcinoma, and it arises in cells that compose tubes in the kidneys and the lining of the bladder and urethra. In this study, the scientists assessed urothelial cells at various stages of disease; some were cancerous and others were pre-cancerous. With whole-genome sequencing and computational tools, the researchers identified genetic mutations and structural variations in DNA that were linked to this type of cancer.

This effort revealed that enzymes called APOBEC3 can create genetic mutations that could lead to bladder cancer development. These enzymes have normally functioned to disable harmful retroviruses by mutating the viral DNA. But these enzymes are also known to mutate other cells' DNA sometimes.

This research has determined that chemotherapy can be a significant driver of genetic errors; cisplatin and other chemotherapies were found to cause additional genetic mutations, some of which probably improve the survival and spread of urothelial cancer cells, even during cancer treatment.

Scientists also revealed that circular fragments of DNA called extrachromosomal DNA (ecDNA) is a significant source of drug resistance in bladder cancer. These ecDNAs are gaining increasing attention in cancer research, and could be major players in cancer development.

The ecDNAs sometimes carry hundreds of copies of growth genes that boost the proliferation of cancer. These molecules are also persistent and complex, and can add even more genetic material after cancer treatment. The study suggested ecDNAs may promote cancer drug resistance.

When a particular gene that regulates the cell cycle was used to engineer an ecDNA, the researchers found that this ecDNA promoted resistance to treatments in the cancer cells that carried it.

“The exact role of APOBEC3-induced mutations in cancer initiation hasn’t been clear,” said co-senior author Dr. Bishoy Faltas, an associate professor at Weill Cornell Medicine, among other appointments.. “But we found that these mutations appear early in urothelial cancer, occurring even in pre-malignant urothelial tissue.”

“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," added study co-author Dr. Olivier Elemento, a professor of physiology and biophysics at Weill Cornell Medicine, among other appointments. “I think this collaboration vindicates that strategy.”

Now the researchers are exploring ways to apply these findings in the clinic, and are searching for methods to block the formation and persistence of ecDNAs.

Sources: Weill Cornell Medicine, Nature