Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets

Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant acti-vation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evi-dence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Automated summary

Basal cell carcinomas (BCCs) are the most common malignant tumors in humans and are usually easily managed by surgery or topical therapies. However, metastatic BCCs are rare and may have distinct biological characteristics. Through genomic profiling, aberrant activation of Hedgehog signaling and alterations in multiple signaling pathways were identified in metastatic BCCs. The presence of clonal origin in matched local recurrences and metastases suggests that molecular profiling can assist in determining the nature and origin of poorly differentiated metastatic tumors. Dysregulation of the Hippo and PI3K/AKT pathways were implicated in the metastatic progression of BCCs, making them potential therapeutic targets.