Study Reveals “Seeds of Skin Cancer” – Gene Mutations Associated with Early Stages of Skin Cancer

PHILADELPHIA – Specific DNA mutations are correlated with the beginnings of squamous cell carcinoma (SCC) and other cancers, according to researchers in the Perelman School of Medicine at the University of Pennsylvania. After using an innovative approach to analyze skin samples and compare them to healthy skin on the same individuals, the team sequenced DNA and found mutations in NOTCH 1-3 – signaling pathways at the cellular level. The researchers also found no cancer-causing mutations in RAS genes, mutations which are common in other forms of cancer and in more progressed SCC, suggesting it’s not a factor in the early development of SCC. The research may illuminate potential ways clinicians can prevent and treat SCC and other skin cancers. The findings were published in the Journal of Investigative Dermatology.

For decades, medical experts have known that UV radiation causes mutations in skin cells that lead to cancers including SCC, which are known to contain more cell mutations than almost all other forms of cancer. Nevertheless, many mutations that have been identified in SCCs are “passenger” mutations, meaning that, while they are present, they don’t appear to cause the cancer. This situation makes it difficult to identify which mutations present in SCCs are important for driving the early stages of UV-induced skin cancer called squamous cell carcinoma in situ (SCCIS).

To identify the mutations associated with SCCIS, a team researchers led by John T. Seykora, MD, PhD, a professor of Dermatology at Penn, analyzed samples using laser-capture microdissection, a way to dissect the skin using a microscope and lasers to make the cut. With this equipment, the investigators were able to precisely identify and isolate SCCIS cells and cut them out of the tissue samples to collect them. Concurrently, the investigators also dissected skin cells from adjacent, healthy-looking skin to serve as a control sample. Following sequencing, the investigators saw NOTCH1, NOTCH2, and NOTCH3 cellular pathways had mutations. Those mutations were then followed by mutations of the TP53 gene.

“Our findings suggest that the NOTCH mutations may be like seeds, encouraged to “grow” into cancer by the later mutation of the TP53 gene,” Seykora said.

Another major finding of this study was that cancer-causing mutations in RAS genes are not found in the early stages of SCC development.

“The fact that they’re not found in those initial growth stages suggests that they’re not the culprits and are not responsible for the formation of squamous cell carcinoma,” Seykora said. “That mutation is likely just a byproduct of the other mutations.”

Knowing what precipitates SCC and other skin cancers and what the skin looks like early on at the cellular level is vital to those researching treatments and prevention. Seykora and his colleagues plan to investigate treatments that could either specifically manipulate or specifically block the effects of the mutated cells or that could prevent the cells from mutating in the first place.

The research team included first author Qi Zheng, PhD, a senior bioinformatician in Dermatology and Brian Capell, MD, PhD, an assistant Professor of Dermatology. Additional Penn authors of the study include Vishwa Parekh, Conor O’Day, Cem Attilasoy, Hasan Bashir, Christopher Yeh, Eun-Hee Shim, Stephen Prouty, Tzevete Dentchev, Vivian Lee, Lily Wushanley, Yerin Kweon, Yoko Suzuki-Horiuchi, Warren Pear and Elizabeth Grice.

The work was supported by the National Institutes of Health (R01 CA165836, P30-CA016520, P30 AR06958901, R01 CA163566, RO1 ES013508 and P30CA016520, K08 EY025742).