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

Nat Commun. 2019 Oct 17;10(1):4717. doi: 10.1038/s41467-019-12746-w.

Abstract

Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • DNA Methyltransferase 3A
  • DNA Mutational Analysis
  • Deubiquitinating Enzyme CYLD / genetics*
  • Deubiquitinating Enzyme CYLD / metabolism
  • Epigenesis, Genetic*
  • Exome Sequencing
  • Female
  • Gene Expression Profiling / methods
  • Humans
  • Male
  • Mutation*
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / metabolism
  • Pedigree
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Retrospective Studies
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism

Substances

  • BCOR protein, human
  • DNMT3A protein, human
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD

Supplementary concepts

  • Familial cylindromatosis