Genomic profiling of metastatic basal cell carcinoma reveals candidate drivers of disease and therapeutic targets

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 activation of Hedgehog signaling, alterations in regulators of GLI transcriptional activity, in kinases and members of Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from three patients provided evidence of a clonal origin in all cases. Mutations in genes associated with YAP inhibition and negative regulation of WNT signaling were found exclusively in hematogenously-spread lung metastases. Metastatic BCCs were enriched for mutations in YAP/TAZ binding domain of TEAD transcriptional factors, RET, HGF and PI3K/AKT signaling compared with an independent cohort of low clinical risk BCCs. Our results implicate Hippo, WNT and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease.EGA study EGAS00001006148