Source of DNA mutations in melanoma

Date:
July 30, 2021
Source:
Van Andel Research Institute
Summary:
The mutations that give rise to melanoma result from a chemical
conversion in DNA fueled by sunlight -- not just a DNA copying error
as previously believed, reports a new study. The findings 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.



FULL STORY ==========================================================================
The mutations that give rise to melanoma result from a chemical conversion
in DNA fueled by sunlight -- not just a DNA copying error as previously believed, reports a study by Van Andel Institute scientists published
today in Science Advances.


==========================================================================
The findings 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. However, in most cases, the source of these
mutations is not clear, which complicates development of therapies and prevention methods," said Gerd Pfeifer, Ph.D., a VAI professor and the
study's corresponding author.

"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 is a serious type of skin cancer
that begins in pigment-producing skin cells. 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 any cancer. Like other skin cancers, melanoma is linked to
sun exposure, specifically a type of radiation called UVB. Exposure to
UVB damages skin cells as well as the DNA within cells.

Most cancers are thought to begin when DNA damage directly causes a
mutation that is then copied into subsequent generations of cells during
normal cellular replication. 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.

DNA comprises 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 of the instructions for life. 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. The resulting instability causes 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 to mutate during normal cell replication,
thereby causing alterations that underlie melanoma.

These mutations may not cause disease right away; instead, they may lay
dormant for years. They also can accumulate as time goes on and a person's lifetime exposure to sunlight increases, resulting in a tough-to-treat
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," 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 findings were made possible using a method developed by Pfeifer's lab called Circle Damage Sequencing, which allows scientists to "break" DNA at each point where
damage occurs. They then coax 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 which DNA bases
are present at the breaks. Going forward, Pfeifer and colleagues plan
to use this powerful technique to investigate other types of DNA damage
in different kinds of cancer.

Other authors include Seung-Gi Jin, Ph.D., Dean Pettinga, Jennifer
Johnson and Peipei Li, Ph.D., of VAI.

========================================================================== Story Source: Materials provided by Van_Andel_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Seung-Gi Jin, Dean Pettinga, Jennifer Johnson, Peipei Li, Gerd P.

Pfeifer. The major mechanism of melanoma mutations is based on
deamination of cytosine in pyrimidine dimers as determined by circle
damage sequencing. Science Advances, 2021; 7 (31): eabi6508 DOI:
10.1126/ sciadv.abi6508 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210730142042.htm

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