The genomic landscape and evolution of cutaneous squamous cell carcinoma

Project Summary/Abstract Cutaneous squamous cell carcinoma is a form of skin cancer, originating from keratinocytes, that kills an estimated 8000 people per year in the United States. Compared to other cancers with similar incidences, death tolls, and/or economic burdens, our understanding of the genomic landscape and genetic evolution of cutaneous squamous cell carcinoma is limited. The overarching goals of this grant are to define the driver mutations in cutaneous squamous cell carcinomas, to delineate the genetic evolution of cutaneous squamous cell carcinomas from precursor lesions, and to establish the earliest genetic alterations occurring in pre- neoplastic keratinocytes. Towards these goals, in aim1, we will identify driver mutations in exome and genome sequencing data covering cutaneous squamous cell carcinoma. This data will be aggregated from publicly available sources as well as new sequencing data from our own institution, collectively comprising the largest analysis of cutaneous squamous cell carcinoma sequencing data to date. In aim2, we will sequence cutaneous squamous cell carcinomas and the remnant precursor lesions from which they arose. Most cutaneous squamous cell carcinomas are discovered adjacent to benign precursor lesions known as actinic keratoses, and here, we will analyze patient-matched lesions to reveal the mutations driving the transition from the benign to the malignant state. In aim3, we will elucidate the earliest somatic alterations occurring in individual keratinocytes from normal skin. Deep sequencing of normal skin has shown that keratinocytes can form patches of related cells, sometimes harboring mutations known to drive cutaneous squamous cell carcinoma, but no studies have truly genotyped keratinocytes at single-cell resolution, leaving gaps in our knowledge of the incipient events that occur in pre-neoplastic keratinocytes. We have developed an innovative workflow to call mutations in individual skin cells with high specificity and sensitivity, permitting us to catalog, for the first time, the genomic alterations in human skin at single-cell resolution. Similar lines of genomic studies have proven fundamental in advancing our understanding of other cancers by revealing therapeutic points of intervention, biomarkers to measure disease progression, biomarkers to estimate disease likelihood, and guidance on the best prevention tactics. Here, we will address these gaps in knowledge for cutaneous squamous cell carcinoma. Taken together, completion of these studies will realize longstanding goals within the field of dermatology, which will pave the way for new treatment strategies and new preventions strategies to alleviate the public health burden posed by cutaneous squamous cell carcinoma.