Mutations in DNA that lead to melanoma result from a sunlight-fuelled chemical conversion in DNA, not just a DNA copying error as previously believed, according to a new study.
The findings of the study, led by the Van Andel Institute scientists and published in Science Advances, upend long-held beliefs about the mechanisms underlying the disease, reinforce the importance of prevention efforts and offer a path forward for investigating the origins of other cancer types.
“Cancers result from DNA mutations that allow defective cells to survive and invade other tissues,” said corresponding author Gerd Pfeifer, PhD, a VAI professor. “However, in most cases, the source of these mutations is not clear, which complicates development of therapies and prevention methods. In melanoma, we’ve now shown that damage from sunlight primes the DNA by creating ‘premutations’ that then give way to full mutations during DNA replication.”
Melanoma begins in pigment-producing skin cells. Although less common than other types of skin cancer, melanoma is more likely to metastasise, significantly reducing patient survival. Previous studies have shown that melanoma has the most DNA mutations of any cancer. Like other skin cancers, melanoma is linked to sun exposure, specifically UVB radiation which damages cells and DNA.
Most cancers are to arise when damaged DNA causes a mutation that is propagated through subsequent cellular generations. In the case of melanoma, however, Pfeifer and his team found a different mechanism that produces disease-causing mutations – the introduction of a chemical base not normally found in DNA that makes it prone to mutation.
In melanoma, the problem occurs when UVB radiation from the sun hits certain sequences of bases: CC, TT, TC and CT, causing them to chemically link together and become unstable. This resulting instability induces a chemical change to cytosine that transforms it into uracil, a chemical base found in the messenger molecule RNA but not in DNA. This change, called a “premutation,” primes the DNA for mutation during normal cell replication and eventually melanoma.
These mutations may lay dormant for years, not causing disease. More mutations can build up throughout a person’s lifetime exposure to sunlight, resulting in a stubborn cancer that evades many therapeutic options.
“Safe sun practices are very important. In our study, 10–15 minutes of exposure to UVB light was equivalent to what a person would experience at high noon, and was sufficient to cause premutations,” Prof Pfeifer said. “While our cells have built-in safeguards to repair DNA damage, this process occasionally lets something slip by. Protecting the skin is generally the best bet when it comes to melanoma prevention.”
The study used a method developed by Prof Pfeifer’s lab called Circle Damage Sequencing, enabling scientists to ‘break’ DNA at each point where damage occurs. DNA is coaxed into circles and replicated with PCR. With enough DNA, next-generation sequencing then identifies which DNA bases are present at the breaks. Pfeifer and colleagues plan to use this technique going forward to examine other types of DNA damage in different kinds of cancer.
Source: Van Andel Institute (VAI)
Journal reference: Jin, S-G., et al. (2021) The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing. Science Advances. doi.org/10.1126/sciadv.abi6508.
