Study reveals source of DNA mutations in melanoma

The mutations that give rise to melanoma result from a chemical conversion of DNA powered by sunlight – not just a DNA copy error as previously believed, reports a study by scientists from the Van Andel Institute published today in Scientists progress.

The findings reverse long-held beliefs about the underlying mechanisms of the disease, reinforce the importance of prevention efforts, and offer a way forward to investigate the origins of other types of cancer.

“Cancers result from mutations in DNA that allow defective cells to survive and invade other tissues. However, in most cases, the source of these mutations is unclear, making development difficult. of therapies and prevention methods, ”said Gerd Pfeifer, Ph.D., VAI professor and corresponding study author. “In melanoma, we have now shown that damage from sunlight prime DNA by creating ‘premutations’ which then give way to complete mutations during DNA replication.”

Melanoma is a serious type of skin cancer that starts in the pigment-producing cells of the skin. Although less common than other types of skin cancer, melanoma is more likely to spread and invade other tissues, which significantly reduces patient survival. Previous large-scale sequencing studies have shown that melanoma has the most DNA mutations of all cancers. Like other skin cancers, melanoma is linked to sun exposure, specifically a type of radiation called UVB. UVB exposure damages skin cells as well as the DNA inside cells.

It is believed that most cancers start when DNA damage directly causes a mutation which is then copied into subsequent generations of cells during normal cell replication. In the case of melanoma, however, Pfeifer and his team have discovered a different mechanism that produces disease-causing mutations: the introduction of a chemical base not normally found in DNA that makes it prone to disease. mutations.

DNA consists of four chemical bases that exist in pairs: adenine (A) and thymine (T), and cytosine (C) and guanine (G). Different sequences of these pairs encode all the instructions of life. In melanoma, the problem arises when UVB radiation from the sun hits certain base sequences – CC, TT, TC, and CT – causing them to chemically bond and become unstable. The resulting instability causes a chemical change in cytosine which turns it into uracil, a chemical base found in the RNA messenger molecule but not in DNA. This change, called a “premutation,” initiates DNA mutation during normal cell replication, causing the changes that underlie melanoma.

These mutations may not cause the disease right away; instead, they can sit dormant for years. They can also build up over time, and a person’s lifetime exposure to sunlight increases, resulting in difficult-to-treat cancer that is beyond many treatment options.

“Safe solar practices are very important. In our study, 10 to 15 minutes of UVB light exposure was equivalent to what a person would experience at full noon and was enough to induce premutations,” Pfeifer said. “Although our cells have protections built in to repair DNA damage, this process sometimes misses something. Protecting the skin is usually the best bet when it comes to preventing melanoma.”

The results were made possible by a method developed by Pfeifer’s lab called Circle Damage Sequencing, which allows scientists to “break” DNA at every point where damage occurs. They then turn the DNA into circles, which are replicated thousands of times using a technology called PCR. Once they have enough DNA, they use next-generation sequencing to identify the DNA bases present at the breaks. In the future, Pfeifer and his colleagues plan to use this powerful technique to investigate other types of DNA damage in different types of cancer.