ULTRAVIOLET LIGHT INDUCED MUTATIONS DRIVES MANY SKIN CANCERS
A genetic mutation
caused by ultraviolet light is likely the driving force behind millions of
human skin cancers, according to researchers at the Stanford University School
of Medicine
The mutation occurs in
a gene called KNSTRN, which is involved in helping cells divide their DNA
equally during cell division.
Genes that cause
cancer when mutated are known as oncogenes. Although KNSTRN hasn't been
previously implicated as a cause of human cancers, the research suggests it may
be one of the most commonly mutated oncogenes in the world.
"This previously
unknown oncogene is activated by sunlight and drives the development of
cutaneous squamous cell carcinomas," said Paul Khavari, MD, PhD, the Carl
J. Herzog Professor in Dermatology in the School of Medicine and chair of the
Department of Dermatology. "Our research shows that skin cancers arise
differently from other cancers, and that a single mutation can cause genomic
catastrophe."
Cutaneous squamous
cell carcinoma is the second most common cancer in humans. More than 1 million
new cases are diagnosed globally each year. The researchers found that a
particular region of KNSTRN is mutated in about 20 percent of cutaneous
squamous cell carcinomas and in about 5 percent of melanomas.
A paper describing the
research will be published online Sept. 7 in Nature Genetics.
Khavari, who is also a member of the Stanford Cancer Institute and chief of the
dermatology service at the Veterans Affairs Palo Alto Health Care System, is
the senior author of the paper. Postdoctoral scholar Carolyn Lee, MD, PhD, is
the lead author.
Lee and Khavari made
the discovery while investigating the genetic causes of cutaneous squamous cell
carcinoma. They compared the DNA sequences of genes from the tumor cells with
those of normal skin and looked for mutations that occurred only in the tumors.
They found 336 candidate genes for further study, including some familiar
culprits. The top two most commonly mutated genes were CDKN2A and TP53, which
were already known to be associated with squamous cell carcinoma.
The third most
commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps
to form the kinetochore -- a structure that serves as a kind of handle used to
pull pairs of newly replicated chromosomes to either end of the cell during
cell division. Sequestering the DNA at either end of the cell allows the cell
to split along the middle to form two daughter cells, each with the proper
complement of chromosomes.
If the chromosomes
don't separate correctly, the daughter cells will have abnormal amounts of DNA.
These cells with extra or missing chromosomes are known as aneuploid, and they
are often severely dysfunctional. They tend to misread cellular cues and to
behave erratically. Aneuploidy is a critical early step toward the development
of many types of cancer.
The mutation in the
KNSTRN gene was caused by the replacement of a single nucleotide, called a
cytosine, with another, called a thymine, within a specific, short stretch of
DNA. The swap is indicative of a cell's attempt to repair damage from
high-energy ultraviolet rays, such as those found in sunlight.
"Mutations at
this UV hotspot are not found in any of the other cancers we
investigated," said Khavari. "They occur only in skin cancers."
The researchers found
the UV-induced KNSTRN mutation in about 20 percent of actinic keratoses -- a
premalignant skin condition that often progresses to squamous cell carcinoma --
but never in 122 samples of normal skin, indicating the mutation is likely to
be an early event in the development of squamous cell carcinomas.
Furthermore,
overexpression of mutant KNSTRN in laboratory-grown human skin cells disrupted
their ability to segregate their DNA during cell division and enhanced the
growth of cancer cells in a mouse model of squamous cell carcinoma.
Finally, Lee compared
five patient-derived squamous cell carcinomas that had the KNSTRN mutation with
five samples that did not have the mutation. Although both sets of cells were
aneuploid, those with the mutation had the most severely abnormal genomes.
The identification of
a new oncogene will allow researchers to better understand how these types of
skin cancers develop. It may also give them clues about how to develop new
therapies for the disease. In this case, it also neatly connects the dots
between sun exposure and skin cancer.
"Essentially, one
ultraviolet-mediated mutation in this region promotes aneuploidy and subsequent
tumorigenesis," said Khavari. "It is critical to protect the skin
from the sun."
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