• Source of DNA mutations in melanoma

    From ScienceDaily@1:317/3 to All on Fri Jul 30 21:30:32 2021
    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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