Patients with recessive dystrophic epidermolysis bullosa (RDEB) frequently develop aggressive, life-threatening cutaneous squamous cell carcinoma (cSCC). Although mechanisms have been proposed to explain why patients suffer this fatal complication, testing such hypotheses requires knowledge of which mutations contribute to the development of RDEB cSCCs. Identifying the mutational landscape of RDEB cSCCs should provide critical insight on how a cancer can develop so quickly in the absence of lifelong sun exposure and DNA damage. Understanding such mechanisms should elucidate modes of prevention and early detection unique to these patients. An increasing number of chemotherapies targeting specific gene mutations are currently in clinical use or development, thus sequencing these cancers may match a known treatment to RDEB patients. This project proposes to sequence 30 RDEB cSCC tumors and matched germ line DNA. This project aims to find tractable therapy options or targets for future development, both clinically and experimentally.