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

Author

Listed:
  • Helen R. Davies

    (Wellcome Trust Sanger Institute
    University of Cambridge
    University of Cambridge)

  • Kirsty Hodgson

    (Newcastle University)

  • Edward Schwalbe

    (Northumbria University
    Newcastle University)

  • Jonathan Coxhead

    (Newcastle University)

  • Naomi Sinclair

    (Newcastle University)

  • Xueqing Zou

    (Wellcome Trust Sanger Institute
    University of Cambridge
    University of Cambridge)

  • Simon Cockell

    (Newcastle University)

  • Akhtar Husain

    (Royal Victoria Infirmary)

  • Serena Nik-Zainal

    (Wellcome Trust Sanger Institute
    University of Cambridge
    University of Cambridge)

  • Neil Rajan

    (Newcastle University
    Royal Victoria Infirmary)

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.

Suggested Citation

  • Helen R. Davies & Kirsty Hodgson & Edward Schwalbe & Jonathan Coxhead & Naomi Sinclair & Xueqing Zou & Simon Cockell & Akhtar Husain & Serena Nik-Zainal & Neil Rajan, 2019. "Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12746-w
    DOI: 10.1038/s41467-019-12746-w
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