A new study identifies the source of DNA alterations in melanoma.

Melanoma mutations are caused by a chemical reaction in DNA fuelled by sunshine, not by a DNA copying error, as previously assumed, according to a study published today in Science Advances by Van Andel Institute scientists.

The findings upend long-held views about the disease’s processes, emphasise the necessity of preventative efforts, and pave the way for future research into the genesis of other cancer types.

“Cancers are caused by DNA abnormalities that enable abnormal cells to survive and invade neighbouring tissues. However, the source of these mutations is frequently unknown, complicating the development of medicines and preventative measures,” said Gerd Pfeifer, Ph.D., a VAI professor and the study’s corresponding author. “We have now demonstrated that UV damage primes the DNA in melanoma by generating ‘premutations,’ which eventually give way to complete mutations during DNA replication.”

Melanoma is a dangerous form of skin cancer that develops in cells that produce pigment. Although melanoma is less prevalent than other types of skin cancer, it is more likely to spread and invade other tissues, reducing patient survival dramatically. Melanoma contains the highest number of DNA alterations of any cancer, according to previous large-scale sequencing studies. Melanoma, like other types of skin cancer, is caused by excessive sun exposure, primarily a form of radiation called UVB. UVB exposure affects both the skin cells and the DNA within the cells.

The majority of cancers are believed to originate when DNA damage directly results in a mutation, which is subsequently replicated in successive generations of cells via normal cellular replication. However, in the case of melanoma, Pfeifer and his colleagues discovered a distinct method by which disease-causing mutations occur — the introduction of a chemical base not ordinarily found in DNA, which makes it mutagenic.

DNA is made up of four chemical bases: adenine (A) and thymine (T), and cytosine (C) and guanine (G) (G). Numerous combinations of these pairs encode all of life’s instructions. Melanoma develops when UVB radiation from the sun interacts with specific base sequences — CC, TT, TC, and CT — causing them to chemically bond and become unstable. As a result of this instability, cytosine undergoes a chemical transition, converting it to uracil, a chemical base found in the messenger molecule RNA but not in DNA. This modification, dubbed a “premutation,” primes the DNA for mutation during regular cell replication, resulting in the changes associated with melanoma.

These mutations may not immediately cause disease, but may remain dormant for years. They can also accumulate over time as a person’s lifetime exposure to sunlight rises, culminating in a difficult-to-treat cancer that is resistant to a wide variety of therapeutic alternatives.

“It is critical to practise safe sun habits. In our study, 10–15 minutes of UVB light exposure was equal to what a person would experience at high noon and was sufficient to induce premutations,” Pfeifer explained. “While our cells have safeguards in place to repair DNA damage, this mechanism occasionally misses something. Generally, protecting the skin is the best course of action when it comes to melanoma prevention.”

The findings were made feasible by Pfeifer’s group using a technique called Circle Damage Sequencing, which enables scientists to “break” DNA at each spot of damage. They then coax the DNA into circular structures that are reproduced millions of times using a technique called polymerase chain reaction (PCR). They employ next-generation sequencing to determine which DNA bases are present at the breaks once they have sufficient DNA. Pfeifer and colleagues intend to employ this effective technology in the future to explore other types of DNA damage in various types of cancer.

Reference
The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing.Seung-Gi Jin1,Dean Pettinga, Jennifer Johnson, Peipei Li and Gerd P. Pfeifer.Science Advances 30 Jul 2021:Vol. 7, no. 31.DOI: 10.1126/sciadv.abi6508