077 Identifying genetic factors that enable basal cell carcinoma to transition from microscopic to macroscopic disease

Basal cell carcinoma (BCC) is driven by constitutive activation of the Hedgehog (Hh) signaling pathway, most commonly through loss-of-function mutations in PTCH1. Using animal models, we demonstrate here that microscopic BCC-like tumors initiated loss Ptch1 or gain Smo fail to progress and eventually enter into a dormant state. Because NOTCH1/2 TRP53 are detected human BCC, sought determine if these genetic factors modulate tumor progression. Indeed, found concomitant either Notch1 Trp53 enables rare macroscopic form. whole exome sequencing IHC, further “successful” acquired ability hyperactivate downstream Hh amplifying Gli1/2 upregulating Mycn. Finally, transgenic overexpression MYCN promotes progression disease. Overall, provide functional evidence BCCs arise step-wise process activate upstream signaling, followed acquisition secondary signaling. Our observations may explain why some persist during pharmacological inhibition SMO highlight as potential target for therapy.