Synergy of TP53 and non-canonical sonic hedgehog pathway in the development of complex basal cell carcinoma

Summary: Abstract Body: Basal cell carcinoma (BCC) is the most common cancer, with an incidence of approximately 3.6 million cases annually in the United States. Common BCC arises in chronically UV-induced damaged skin. Although the main driver oncogenes in common BCC include mutations in Sonic Hedgehog (SHH) pathway, a rare subset of aggressive and complex BCCs exhibits mutations in non-canonical pathways in synergy with TP53 mutations, in addition to other well studied oncogenes that are also involved in highly aggressive and potentially deadly pancreatic or renal carcinomas among others. Not only do complex BCC differ from the common ones in clinical presentation, but they also differ in treatment-resistant course of the disease to Hedgehog inhibitors (HHI) due to lack of PTCH mutations, which is the main driver oncogene in common BCC. Although complex BCC stems from the basal layer, hence presenting histologically similar to other BCCs, these patients experience a clinically divergent course of the disease that is complex, destructive, and highly aggressive. This warrants genomically driven and timely personalized or targeted treatment planning to avoid disfiguration and to save lives. Thus was performed a bioinformatic analysis of whole exome genomics of ten complex BCCs acompanied by correlated immunohistochemistry compared with five common BCCs. Our preliminary findings are indicative of a synergistic interplay of TP53, non-canonical SH pathways, with other aggressive driver oncogenes seen in other more deadly carcinomas such as pancreatic and renal. Understanding the genomics in these BCC subsets has guided a more promising treatment plan in presenting patients. Sophia V. Gandarillas¹, Darius Mehregan², Adam Berger³, Bahar Dasgeb³ 1. Wayne State University School of Medicine, Detroit, MI, United States. 2. Dermatology, Wayne State University School of Medicine, Detroit, MI, United States. 3. Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States. UV Biology/Injury and Non-melanoma Cancers