Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome

Area of Science:

• Oncology
• Genetics
• Dermatology

Background:

• CYLD cutaneous syndrome (CCS), also known as Brooke-Spiegler syndrome, is characterized by germline mutations in the CYLD tumor suppressor gene.
• Patients with CCS develop multiple skin tumors with varied histophenotypes.

Purpose of the Study:

• To comprehensively profile the genomic landscape of tumors in individuals with CYLD cutaneous syndrome.
• To identify genetic alterations and understand the mechanisms driving tumorigenesis and metastasis in CCS.

Main Methods:

• Genomic profiling of 42 benign and malignant tumors from 13 individuals across four families.
• Multi-level and microdissected sampling for detailed clonal analysis.
• Integrated genomic, methylation, and transcriptomic profiling.

Main Results:

• Recurrent mutations in epigenetic modifiers DNMT3A and BCOR were identified in 29% of benign tumors.
• Intra-tumor heterogeneity was observed, with multiple clones harboring different DNMT3A mutations within benign tumors.
• Isoform-specific DNMT3A2 mutations were linked to aberrant DNA methylation patterns.
• Phylogenetic and mutational signature analyses confirmed pulmonary metastasis of cylindromas from primary skin tumors.

Conclusions:

• The study reveals frequent mutations in epigenetic modifiers DNMT3A and BCOR in benign CCS tumors.
• Intra-tumor heterogeneity is a common feature in CCS tumorigenesis.
• Aberrant methylation and specific DNMT3A2 mutations contribute to tumor development.
• Findings elucidate pathways of cutaneous tumorigenesis and metastasis in CCS.