Cutaneous carcinosarcoma: further insights into its mutational landscape through massive parallel genome sequencing

Area of Science:

• Oncology
• Genetics
• Dermatopathology

Background:

• Cutaneous carcinosarcoma (CCS) is an exceptionally rare neoplasm.
• CCS presents a biphasic morphology with both epithelial and sarcomatoid components.
• The histogenesis and biological behavior of CCS are poorly understood, with theories suggesting a single cancer stem cell origin.

Purpose of the Study:

• To investigate the mutational landscape of cutaneous carcinosarcoma (CCS).
• To determine if the epithelial and sarcomatoid components of CCS share common genetic signatures.
• To explore potential correlations between molecular alterations and the epithelial morphotype of CCS.

Main Methods:

• High-depth next-generation sequencing (NGS) was performed on 47 cancer-associated genes.
• Mutational hot spot regions were analyzed in both epithelial and sarcomatoid components of CCS.
• Genetic signatures of distinct tumor elements were compared to assess clonal origin.

Main Results:

• Both epithelial and sarcomatoid components of CCS share a common clonal origin, despite phenotypic differences.
• CCS exhibits molecular heterogeneity, with distinct mutational profiles associated with specific epithelial morphotypes.
• Squamous cell carcinoma-like CCS shows TP53 gene mutations, while basal cell carcinoma-like CCS has a more complex mutational landscape.

Conclusions:

• Cutaneous carcinosarcomas arise from a common progenitor cell.
• Specific molecular signatures correlate with the epithelial differentiation of CCS, indicating distinct subtypes.
• The identified targetable gene pathways offer potential for developing personalized therapies for CCS.