Does Basal Cell Carcinoma Arise from a Precursor Lesion?

Basal cell carcinoma (BCC) is driven in nearly all cases by mutations that constitutively activate upstream Hedgehog (HH) signaling, either through loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO. Unlike other skin cancers such as squamous cell carcinoma, a clinically apparent precursor lesion for BCC has not been identified. Recent genomic analyses of both human and mouse tumors suggest that BCC formation requires not only PTCH1 or SMO mutations but also additional genetic changes. These findings imply that some BCCs may follow a stepwise tumor progression model, whereby the accumulation of multiple mutational "hits" is needed to convert an indolent precursor lesion into malignant disease. On the basis of studies in patients with Gorlin syndrome who harbor germline PTCH1 mutations and are genetically predisposed to forming BCC, we speculate that at least a subset of BCCs arises from a subclinical basaloid follicular hamartoma or similar precursor lesion. Altogether, convergent evidence suggests that activating upstream HH signaling is necessary but not sufficient for BCC formation. This evolving view of BCC has important implications for our basic understanding of these tumors, for our interpretation of findings from BCC mouse models, and for guiding treatment.