Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCC). The molecular etiology of RDEB SCC, which arise at sites of sustained tissue damage, is unknown. We performed whole exome and RNA sequencing, revealing an accelerated endogenous mutation rate and APOBEC mutation signatures increased throughout tumor evolution, relative to spontaneous, cutaneous SCC. RDEB SCC also exhibit genomic mutational patterns confirming nucleotide-excision competence, supporting a model in which early onset of malignancy is caused primarily by increased mutagenesis. Interestingly, a subset of non-RDEB, HPV-negative head-and-neck SCC also show enhanced APOBEC signatures, suggesting this mechanism is important in specific SCC subtypes. Collectively, these data reveal a mutagenic mechanism associated with chronic tissue damage, suggesting a cause for cancers arising at sites of persistent inflammation.

Accelerated endogenous mutation rate drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa