Scientists have discovered a new oncogene, KNSTRN, which accelerates the development of cutaneous squamous cell carcinoma.

Scientists have discovered a new oncogene for cutaneous squamous cell carcinoma (SCC), the second most common skin cancer. The oncogene, known as KNSTRN, appears to be mutated by exposure to UV light (Nat Genet 2014;46:1060–2).

“Finding a new oncogene was very exciting,” says Carolyn Lee, MD, PhD, a clinical instructor in dermatology at the Stanford University School of Medicine in Palo Alto, CA, and the study's lead author. “It's important for our understanding of how SCC tumors develop, and it may eventually provide insight into molecular mechanisms with therapeutic implications.”

Lee and her colleagues hit on KNSTRN while investigating genetic causes of cutaneous SCC. They performed whole-exome sequencing on a series of SCCs and patient-matched normal skin samples, yielding a set of 336 candidate cancer genes. They then sequenced these 336 genes in another set of 100 cutaneous SCCs and patient-matched normal skin cells in a targeted search for SCC-associated mutations.

The three most frequently mutated genes included the well-known tumor suppressor genes TP53 and CDKN2A, as well as KNSTRN, a “gene that we were unfamiliar with,” Lee says.

The mutational patterns the scientists found were “characteristic of exposure to UV light,” which is consistent with well-established data linking SCC to sun exposure. In addition, the mutations clustered in an N-terminal region, including a “hotspot” substitution of phenylalanine for serine at codon 24.

That the mutations clustered in one place provides evidence that KNSTRN is an oncogene, according to Lee. Mutations in tumor suppressor genes, such as the BRCA genes implicated in breast and ovarian cancers, usually scatter evenly throughout the gene, she explains, whereas in oncogenes, they more often accumulate in hotspots.

What little data are available on kinastrin function suggest it normally modulates the segregation of chromosomes during mitosis. Lee's new findings suggest that mutant kinastrin disrupts sister chromatid cohesion and chromosome segregation, and may result in aneuploidy.

To investigate the gene's oncogenic potential, Lee and her colleagues introduced normal and mutated KNSTRN into normal human skin cells. They found that the mutated gene disrupts chromosome segregation during cell division. More direct evidence that mutant KNSTRN is tumorigenic came when they found that it accelerates tumor growth in a mouse model of cutaneous SCC. Lee's search of publicly available TCGA data suggests KNSTRN might also play a role in melanoma, but she says its potential role in other cancers isn't known.

Kenneth Tsai, MD, PhD, a dermatologist and researcher at The University of Texas MD Anderson Cancer Center in Houston who is not affiliated with the study, says the discovery that a single UV-mediated point mutation can turn KNSTRN into an oncogene that accelerates cutaneous SCC tumor growth is important, particularly because other well-known oncogenes such as mutant RAS are not found with high frequency in the disease in humans.

“What we need now is a deep characterization of its function in the cell,” he says, “and then we need to figure out how to disable it.”

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