Subtype-Specific Analyses Reveal Infiltrative Basal Cell Carcinomas Are Highly Interactive with their Environment

Area of Science:

• Dermatology
• Oncology
• Molecular Biology

Background:

• Basal cell carcinoma (BCC) comprises subtypes with distinct clinical behaviors.
• Infiltrative BCCs exhibit poorer therapeutic responses and higher dissemination risk compared to other subtypes.
• Molecular distinctions driving these differences remain largely unknown.

Purpose of the Study:

• To identify somatic mutations and molecular pathways associated with infiltrative BCC.
• To elucidate the molecular basis for the aggressive phenotype of infiltrative BCCs.

Main Methods:

• Whole-exome sequencing (WES) and RNA sequencing were performed on BCC samples.
• Combined WES data from 36 new samples and 58 previously reported samples.
• Differential gene expression analysis and immunostaining for key proteins (periostin, WISP1, β-catenin).

Main Results:

• Infiltrative BCCs share common UV-induced mutational signatures and lack distinct somatic variant profiles.
• RNA sequencing identified increased expression of POSTN and WISP1, indicating elevated integrin and Wnt signaling.
• Immunostaining confirmed higher periostin and WISP1 levels and increased nuclear β-catenin in infiltrative BCCs.
• Mixed-morphology BCCs showed WISP1 expression in infiltrative areas but not nodular areas.

Conclusions:

• Infiltrative BCCs are not initiated by unique genomic alterations.
• A distinct extracellular matrix interaction profile, regulating Wnt signaling, characterizes infiltrative BCCs.
• These findings suggest a molecular continuum between BCC subtypes, driven by microenvironmental interactions.