Study Examines Link Between Squamous Cell Carcinoma and Recessive Dystrophic Epidermolysis Bullosa

Key Points

  • DNA changes from APOBEC accounted for 42% of mutations in RDEB skin tumors. In most people with skin cancer, APOBEC is much less active, making up about only about 2% of the mutations in tumors.
  • RDEB skin cancers share more genetic mutations in common with cancers that develop in the oral cavity than cancer that develops in the skin from ultraviolet exposure.
  • Future research plans to focus on what turns APOBEC enzymes on and to look for compounds that disable them.

Many patients with the rare skin disease recessive dystrophic epidermolysis bullosa (RDEB)—commonly called butterfly syndrome—also develop squamous cell carcinoma early in life. Now an international team of scientists led by researchers at the Sidney Kimmel Cancer Center–Jefferson Health has found that immune system–related enzymes are major contributors to the development of this cancer. The discovery identifies new therapeutic strategies and reveals how chronic inflammation can spur cancer. These findings were published by Cho et al in Science Translational Medicine.

“We’re describing for the first time a mechanism that instigates tissue damage–driven cancers,” said senior author Andrew South, PhD, Associate Professor in the Department of Dermatology and Cutaneous Biology at Jefferson.

Dr. South studies RDEB, a genetic disease that makes the skin extremely fragile—even the slightest touch can cause damage, as the condition results from mutations in a gene that helps to hold layers of the skin together. A small scratch or brush of the skin can easily separate the layers and cause blisters that do not heal well. This often leads to considerable scarring.

Squamous cell carcinoma develops in tissues that act as a barrier to the environment such as the skin, but also the oral cavity, lungs, and cervix. Many people develop this kind of cancer in their skin from sun exposure, and when detected early, squamous cell carcinoma of the skin is curable. But that’s not the case for patients with RDEB—their 5-year survival rate is close to zero.

Dr. South and colleagues wanted to explore why the cancer is so frequent in patients with RDEB, and what makes it so aggressive. He reached out to labs and clinics around the world that treat these patients to collect as many RDEB squamous cell carcinoma samples as possible, including theDEBRA Adult EB and Skin Cancer Clinic.

Study Findings

When the researchers examined the genetic sequences of patients with RDEB-related tumors, they found that a group of enzymes called apolipoprotein B editing complex (APOBEC) caused a large proportion of the cancer’s mutations. These proteins help the immune system by editing nucleic acid messages in pathogens. When APOBEC enzymes edit DNA’s messages, for example, they increase the diversity of antibodies available to fight off infection. In patients with RDEB, inflammation from continued tissue damage and the persistent threat of microbial infection increases APOBEC expression, leading the enzymes to attack the patient’s DNA, which then creates cancer-causing mutations.

In fact, DNA changes from APOBEC accounted for 42% of mutations in RDEB skin tumors. In most people with skin cancer, APOBEC is much less active, making up only about 2% of the mutations in tumors. The finding means these APOBEC alterations distinguish RDEB skin cancer from the kind caused by sunlight. And since RDEB skin tumors develop in places with chronic wounds, the discovery further provides a mechanism for how inflammation and tissue damage spur cancer progression.

“We show for the first time that a different mutational process appears to promote cancers caused by chronic tissue damage, as observed in RDEB. This is potentially an invisible force that also contributes to a much broader range of cancers,” said first author Raymond Cho, MD, PhD, a University of California, San Francisco (UCSF) Health dermatologist and Associate Professor in the Department of Dermatology at UCSF. 

Dr. South and colleagues then looked at which genes turn off or on and by how much in RDEB skin tumors compared to squamous cell carcinomas in other tissues. When the researchers grouped genes that perform similar biologic functions together, they discovered RDEB skin cancers share more in common with those that develop in the oral cavity than cancer that develops in the skin from ultraviolet exposure. 

Previous research has shown that like RDEB skin cancer, squamous cell carcinoma in the oral cavity is more aggressive than in the skin and also has more APOBEC mutations. Together with these earlier findings, Dr. South’s discovery suggests therapeutic approaches for oral cancer might be effective against RDEB skin cancers.

“We should be treating those cancers in patients [with RDEB] similarly to how we treat cancer in the oral cavity,” said Dr. South. “That's a direct clinical outcome from this research.”

As a result of the new work, the Department of Defense recently awarded Dr. South with a grant to study what turns APOBEC enzymes on and to look for compounds that disable them. “Such inhibitors could be used to help prevent mutation acquisition and skin cancer development in [patients with] RDEB,” said Dr. South.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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