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

Helen R. Davies, Kirsty Hodgson, Edward Schwalbe, Jonathan Coxhead, Naomi Sinclair, Xueqing Zou, Simon Cockell, Akhtar Husain, Serena Nik-Zainal () and Neil Rajan ()
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Helen R. Davies: Wellcome Trust Sanger Institute
Kirsty Hodgson: Newcastle University
Edward Schwalbe: Northumbria University
Jonathan Coxhead: Newcastle University
Naomi Sinclair: Newcastle University
Xueqing Zou: Wellcome Trust Sanger Institute
Simon Cockell: Newcastle University
Akhtar Husain: Royal Victoria Infirmary
Serena Nik-Zainal: Wellcome Trust Sanger Institute
Neil Rajan: Newcastle University

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12746-w

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DOI: 10.1038/s41467-019-12746-w

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