Genomic Stability in Syndromic Basal Cell Carcinoma

Area of Science:

• Oncology
• Genetics
• Dermatology

Background:

• Basal cell cancers (BCCs) often involve Hedgehog pathway activation.
• SMO inhibitors, like vismodegib, treat advanced BCCs.
• Basal cell nevus syndrome (BCNS) involves germline PTCH1 defects and numerous BCCs, which respond better to SMO inhibitors than sporadic BCCs.

Purpose of the Study:

• To characterize BCCs in BCNS patients.
• To understand the molecular differences between BCNS-BCCs and sporadic BCCs.
• To explain the differential response to SMO inhibitors.

Main Methods:

• Comparative genomic analysis of BCCs from BCNS patients and sporadic BCCs.
• Assessment of somatic mutation load and UV mutagenesis signatures.
• Evaluation of SMO mutation status and genomic stability.

Main Results:

• BCNS-BCCs have significantly lower mutational load and UV mutagenesis compared to sporadic BCCs.
• BCNS-BCCs exhibit increased genomic stability and fewer baseline SMO resistance mutations.
• Individuals with lower tumor burden in BCNS showed fewer UV mutations, suggesting UV's role.

Conclusions:

• BCNS-BCCs possess a reduced mutator phenotype, contributing to their indolent course.
• Lower intrinsic resistance mechanisms in BCNS-BCCs explain their heightened sensitivity to SMO inhibitors.
• Genomic differences underscore the distinct biology of BCCs in BCNS.