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Study Discovers Link Between Butterfly Syndrome and Skin Cancer

Investigators have discovered an important link between recessive dystrophic epidermolysis bullosa and squamous cell carcinoma, suggesting a new approach to treatment.

An international team of investigators has made a discovery about the cause of autosomal recessive dystrophic epidermolysis bullosa (RDEB) that sheds light on how the disease leads to cancer in some patients and offers clues to potential new approaches to treatment.

Also known as butterfly syndrome, RDEB is a rare genetic condition affecting the skin, causing it to blister and easily form erosions from minor injuries such as scratching or rubbing. According to the National Institutes of Health (NIH), the overall estimated incidence of dystrophic epidermolysis bullosa in the United States is 6.5 per million newborns, with more severe autosomal recessive forms of the disease occurring in 1 per million newborns. In cases of the most severe form of the condition, Hallopeau-Siemens type RDEB (RDEB-HS), infants are often born with widespread skin blistering and erosion occurring during birth. Healing skin develops severe scarring, and, along with other complications, patients with the disease are at high risk for developing an aggressive form of squamous cell carcinoma (SCC) as young adults.

Investigators have linked all major forms of dystrophic epidermolysis bullosa to mutations in the COL7A1 gene, which provides instructions for making a protein that is used to assemble type VII collagen, essential to the structure and strength of connective tissues such as skin, tendons, and ligaments. Type VII collagen is also key to the connection between the epidermis and the dermis. In a study recently published in the journal Science Translational Medicine, an international research team led by scientists from the Sidney Kimmel Cancer Center—Jefferson Health investigated why skin cancer is so prevalent in RDEB patients and why it’s so deadly in those with the disease. While SCC caused by sun exposure is relatively curable, patients with RDEB-associated skin cancer have a very low 5-year survival rate.

Clinics from around the world treating RDEB patients contributed squamous cell carcinoma samples for the study. The research team studied the genetic sequences of the tumors and discovered that many of the cancer’s mutations were caused by a group of enzymes called apolipoprotein B editing complex (APOBEC). In individuals with RDEB, inflammation from persistent tissue damage and skin infection increases APOBEC expression. In turn, the enzymes attack the DNA, forming cancer-causing mutations. Sixty-seven percent of RDEB SCC driver mutations were found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, according to the study’s findings.

“We’re describing for the first time a mechanism that instigates tissue damage-driven cancers,” explained senior author Andrew South, PhD, in a recent statement, on the significance of the discovery. In additional findings, the research team found that SCC in RDEB patients are actually more similar to oral cavity cancers than the skin cancers caused by sun exposure, explaining the aggressive nature of RDEB SCC. “We should be treating those cancers in the RDEB patients similarly to how we treat cancer in the oral cavity,” Dr. South added. “That's a direct clinical outcome from this research.”

Since this study, Dr. South has received a $1.75 million grant from the Department of Defense to study what turns on APOBEC enzymes and if there are compounds to disable them. In an interview with Rare Disease Report ®, Dr. South discussed the search for such inhibitors, which could be used to help prevent mutation acquisition and skin cancer development in RDEB patients.

“We are looking at whether inflammatory cytokines switch APOBEC enzymes on in RDEB skin cells, but the data are too preliminary to comment on,” he explained. “We are screening multiple different patients to get an accurate and consistent picture.”

Feature Picture Source: CDC / Dr. Hudson / CDC Public Health Image Library. Picture Caption: This image depicts the lower extremities of a young patient revealing bullous erythematous lesions due to a condition known as epidermolysis bullosa (EB). In the foreground, the left lateral thigh, lower leg and foot display lesions, and in the background the right medial thigh exhibits a lesion.