BCC development in mice is driven by acquired genomic alterations that increase hedgehog pathway activity

Summary: Abstract Body: Constitutive Hedgehog (Hh) pathway activity, driven by loss-of-function PTCH1 mutation or gain-of-function SMO mutation, is a molecular hallmark of basal cell carcinoma (BCC). Both alterations lead to activation of GLI transcription factors in mice and development of microscopic follicular hamartomas, whereas skin-targeted overexpression of GLI2 also drives robust nodular BCC development. Despite widespread expression of GLI2 in K5-Gli2 mice, BCC development is focal and takes 4-5 months, with tumors displaying markedly higher Hh signaling than the background of slow-growing benign follicular hamartomas where they arise. We performed whole exome sequencing on 8 nodular BCCs from K5-Gli2 mice to shed light on the potential molecular mechanism underlying progression from hamartoma to BCC. The BCC genomes were nearly diploid with low tumor mutational burden. Six tumors (75%) carried focal amplification of endogenous Gli2 on Chr 1, and five tumors (63%) had lost all or most of one copy of Chr 19, which includes the Hh pathway repressor and tumor suppressor Sufu. Strikingly, homozygous K5-Gli2 mice developed macroscopic BCCs with shorter latency and markedly higher numbers than heterozygous mice, underscoring the importance of elevated Hh/Gli2 signaling in driving macroscopic tumor development. Our data support the emerging concept that macroscopic BCC development is a multi-step process involving acquired alterations in Hh pathway genes leading to high-level oncogenic Hh signaling, and that follicular hamartomas may be precursor lesions for some BCCs. Elisabeth A. Pedersen¹, Marina Grachtchouk¹, Natalia A. Veniaminova¹, Monique Verhaegen¹, Paul Harms^{1, 2}, Sunny Wong^{1, 3}, Marcin Cieslik², Andrzej Dlugosz^{1, 3} 1. Dermatology, University of Michigan Michigan Medicine, Ann Arbor, MI, United States. 2. Pathology, University of Michigan Michigan Medicine, Ann Arbor, MI, United States. 3. Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, United States. UV Biology/Injury and Non-melanoma Cancers