According to recent research conducted by Van Andel Institute researchers, the mutations giving rise to melanoma are the outcome of a chemical conversion in DNA triggered by sunlight, and not just a DNA copying error as believed earlier.
Dr Gerd Pfeifer. Image Credit: Van Andel Institute.
The results of the study, published recently in the journal Science Advances, transpose the conviction on the mechanisms underlying the disease, reinforce the significance of prevention efforts, and provide a way ahead for examining the origins of other types of cancer.
Cancers result from DNA mutations that allow defective cells to survive and invade other tissues. 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.”
Gerd Pfeifer, PhD, Study Corresponding Author and Professor, Van Andel Research Institute
Melanoma, a serious skin cancer type, starts in pigment-producing skin cells. Melanoma is less common than other skin cancer types, but it is more likely to spread and invade other tissues, which substantially decreases patient survival. Earlier large-scale sequencing studies have shown that melanoma has the most DNA mutations of any cancer.
Similar to other skin cancers, melanoma is linked to sun exposure, especially a kind of radiation called UVB. Exposure to UVB damages skin cells along with the DNA within cells.
It is anticipated that most cancers begin when DNA damage directly makes a mutation that is then copied into the next generations of cells during normal cellular replication. However, in melanoma, Pfeifer and his associates identified a different mechanism that creates disease-causing mutations—the introduction of a chemical base not generally found in DNA makes it susceptible to mutation.
DNA has four chemical bases that exist in pairs—adenine (A) and thymine (T), cytosine (C) and guanine (G). Various sequences of these pairs encode all of the instructions for life. In melanoma, the problem appears when UVB radiation from the sun hits specific sequences of bases—CC, TT, TC, and CT—making them chemically link together and thus become unstable.
The resultant instability makes 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, known as “premutation,” primes the DNA to mutate at the time of normal cell replication, making alterations that underlie melanoma.
The mutations probably do not cause disease right away; on the contrary, they lie dormant for years. These mutations also accumulate with time depending on an individual’s lifetime exposure to sunlight, resulting in difficult-to-treat cancer that escapes numerous 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. 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.”
Gerd Pfeifer PhD, Study Corresponding Author and Professor, Van Andel Research Institute
The research outcome was achieved with a method created by Pfeifer’s lab, called Circle Damage Sequencing, which allows researchers to “break” DNA at each point where damage occurs.
They then coax the DNA into circles and replicate it thousands of times using a technology called PCR. When the researchers got the desired amount of DNA, they employed next-generation sequencing to determine the DNA bases that are present at the breaks.
Pfeifer and co-workers intend to use this powerful method to analyze other types of DNA damage in different types of cancer.
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.