Genetic research sheds light on how sunlight drives skin cancer

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Paul A. Khavari, MD, PhD

Decades of research into the human genome has taught researchers not only how normal cells evolve into skin cancer cells, but why. The answer — sunlight — is not a surprise for dermatologists.

That message was delivered by dermatologist and skin cancer researcher Paul A. Khavari, MD, PhD, Sunday during the Lila and Murray Gruber Memorial Cancer Research Award and Lectureship, “Pathogenesis of Skin Cancer.”

“Sequencing the genomes of hundreds of squamous cell carcinomas (SCCs) has revealed the enormous number of UV-induced mutations that characterize these cancers,” Dr. Khavari said in an interview before his lecture. “An increasingly clear understanding is emerging of which genes are recurrently damaged by sunlight and how they cooperate to convert normal skin into cancer.

“We as dermatologists have long been rightly fearful of too much sun exposure because of skin cancer and photoaging. But now, in the case of cutaneous SCC, we are gaining a clearer picture of who the key actors are and how they connect to fundamental principles of carcinogenesis. These recent advances underscore how important it is that we be informed of the dangers of sunlight at a specific level and really work hard to encourage protection against sunlight-induced mutagenesis.”

Years of research have demonstrated that cancers arise from cells that fail to differentiate normally and then go on to keep proliferating in an undifferentiated state, said Dr. Khavari, professor and chairman of the department of dermatology at Stanford University School of Medicine and the chief of the dermatology service at the VA Palo Alto Health Care System. He and his team have gained insight into SCC by sequencing more than 300 specimens of tumors and their matched normal control skin.

“Sunlight-induced mutations lead to a loss of normal differentiation, caused by inactivation of the Notch pathway, and a hyperactivation of cell division, caused by activation of a number of pathways, including the Ras-Raf-MAP kinase pathway, that drives the cells to divide,” he said. “All of that unfolds in the context of genomic damage that engages additional pro-cancer mechanisms.”

Regarding genomic damage, the Stanford group also discovered a new sunlight-specific oncogene that is specific to skin. Known as kinastrin, this gene displayed UV-signature point mutations only in skin cancers, including SCC, melanoma, and advanced basal cell carcinoma, but not in visceral cancers. Surprisingly, a single UV-induced point mutation in kinastrin led to massive DNA damage known as aneuploidy, a condition known to accelerate tumorigenesis.

“These new findings highlight the potential for therapies targeting aneuploid cells in the skin,” Dr. Khavari said. “However, surgical therapy remains by far the best therapy for primary SCC, and will be for the foreseeable future.”

For now, the key lesson learned from genetic research is that sun exposure over decades causes a set of specific gene mutations that cooperate to set the stage for the development of cancer.

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