Does Basal Cell Carcinoma Arise from a Precursor Lesion?

Area of Science:

• Oncology
• Dermatology
• Genetics

Background:

• Basal cell carcinoma (BCC) is primarily driven by mutations activating the Hedgehog (HH) signaling pathway.
• Unlike other skin cancers, BCC lacks a clearly identifiable precursor lesion.
• Genomic studies indicate that BCC formation involves multiple genetic alterations.

Purpose of the Study:

• To explore the genetic underpinnings of Basal cell carcinoma (BCC) development.
• To investigate the role of additional genetic changes beyond Hedgehog pathway activation in BCC formation.
• To propose a stepwise tumor progression model for BCC.

Main Methods:

• Analysis of genomic data from human and mouse BCC tumors.
• Review of studies on Gorlin syndrome patients with germline PTCH1 mutations.
• Integration of convergent evidence from various research findings.

Main Results:

• BCC development necessitates both Hedgehog pathway activation (via PTCH1 or SMO mutations) and other genetic changes.
• A stepwise tumor progression model, involving accumulation of multiple mutations, is suggested for BCC.
• Subclinical precursor lesions, such as basaloid follicular hamartomas, may precede BCC formation in some cases.

Conclusions:

• Hedgehog pathway activation is a necessary but insufficient driver for Basal cell carcinoma (BCC) development.
• The findings support a multi-step carcinogenesis model for BCC.
• This understanding impacts basic research, mouse models, and therapeutic strategies for BCC.