Yet Another Genetic Reason to Protect Skin From Sun

Pam Harrison

September 08, 2014

A previously unknown oncogene that is activated by ultraviolet (UV) light has been implicated in a considerable proportion of squamous cell carcinomas (SCCs) and in some melanomas as well, a new study shows.

The research was published online September 7 in Nature Genetics.

A team from the Stanford University School of Medicine and from the Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, identified recurrent point mutations concentrated at an UV signature "hotspot" in KNSTRN, a gene involved in helping cells divide their DNA equally during cell division, in 17% of SCCs analyzed by whole-exome sequencing and 19% of SCCs analyzed by targeted sequencing.

The same KNSTRN mutation was identified in approximately 5% of all melanomas sequenced as well.

"Mutations at this UV hotspot are not found in any of the other cancers investigated — they occur only in skin cancers," senior author Paul Khavari, MD, PhD, professor of dermatology, Stanford University School of Medicine, said in a briefing.

"And this study highlights the importance of sun protection," he told Medscape Medical News, "because it makes it clear that a single mutation in a single gene can start a process of catastrophe for the genome, which has real implications for how careful people should be about the sun, even more than we ever suspected."

 
[T]his study highlights the importance of sun protection… Dr. Paul Khavari
 

To identify recurrent genomic aberrations that underlie the development of SCC, investigators used single-nucleotide variant determinations from whole-exome sequencings of 12 SCC–normal pairs. From this work, they distilled 336 candidate genes that were subsequently resequenced in 100 matched SCC–normal pairs as well as in 5 SCC cell lines.

"Analysis of mutation type showed that the majority of tumors had mutational profile characteristics of exposure to ultraviolet light," investigators point out. As Dr. Khavari explained to Medscape Medical News, UV light enters the body's cells with a very high energy that damages DNA.

"Once the DNA is damaged, it needs to be repaired," he added, "and that repair process is not always perfect." If, for example, the damaged DNA is repaired with an "G" instead of an "A" required for the repair "that can lead to mutations that are stably inherited by that cell's progeny, which then can go on to help it become cancer."

Several other mutations, including the TP53 and the CDKN2A mutations, were identified in the same sequences, but both had been previously associated with SCC.

However, the third mutated gene, the KNSTRN gene, was somewhat of a surprise. As investigators explain in the briefing, KNSTRN encodes a protein that helps form the kinetochore, a structure that serves as a "handle" that is 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 2 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.

Researchers subsequently observed that overexpression of the mutant KNSTRN gene 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 SCC.

Early Event

To determine whether KNSTRN mutagenesis might be an early event in SCC development, researchers screened 38 additional primary SCCs as well as 27 actinic keratoses, the earliest SCC precursors, for the same mutation.

They again detected KNSTRN in 13% of the additional SCCs and in 19% of the actinic keratoses. Using available data sets from The Cancer Genome Atlas, researchers also identified the KNSTRN mutation in 23 of 490 sequenced melanomas (4.7%), another major sunlight-assigned cancer, as they observe.

In contrast, KNSTRN was never identified in 122 samples of normal skin, a sign that the mutation arises early in tumorigenesis, as researchers point out.

Lastly, investigators compared 5 patient-derived SCCs that carried the KNSTRN mutation with 5 samples that did not. Both sets of cells were aneuploid (having an abnormal chromosome number), as they reported. But cells with the mutation had the most severely abnormal genomes.

Taken together, these findings suggest a UV light–mediated mutation largely confined to a specific region of the gene that promotes aneuploidy and subsequent tumorigenesis.

"Sunscreen has been shown to prevent damage to the skin that happens from UV light and so sunscreen should help prevent this mutation and any other mutation associated with skin cancer," Dr. Khavari emphasized.

"And anything that can reduce the amount of UV injury from the sun will not only decrease the incidence of cancer and cancer-causing mutations but will also help the skin age less quickly because both skin cancer and skin aging are related to UV injury. It is critical to protect the skin from the sun."

The study was supported by the National Institutes of Health and the US Veterans Affairs Office of Research and Development. The authors have disclosed no relevant financial relationships.

Nature Genet. Published online September 7, 2014. Abstract

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