076 Subtype specific analyses reveal infiltrative basal cell carcinoma are highly interactive with their environment

Little is known regarding the molecular differences between BCC subtypes, despite clearly distinct phenotypes and clinical outcomes. In particular, infiltrative BCCs have poorer clinical outcomes in terms of response to therapy and propensity for dissemination. In this project we aimed to use exome sequencing and RNA sequencing to identify somatic mutations and molecular pathways leading to infiltrative BCCs. Using whole exome sequencing of 36 BCC samples (8 infiltrative) combined with previously reported exome data (58 samples), we determine that infiltrative BCC do not contain a distinct somatic variant profile and carry classical UV induced mutational signatures. RNA sequencing on both datasets revealed key differentially expressed genes such as POSTN and WISP1 suggesting increased integrin and Wnt signalling. Immunostaining for POSTN and WISP1 clearly distinguished infiltrative BCCs and nuclear beta-catenin staining patterns further validated the resulting increase in Wnt signalling in infiltrative BCCs. Of significant interest, in BCCs with mixed morphology, infiltrative areas expressed WISP1 while nodular areas did not, supporting a continuum between subtypes. In conclusion, infiltrative BCCs do not differ in their genomic alteration in terms of initiating mutations. They display a specific type of interaction with the extracellular matrix environment regulating Wnt signalling.