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

Lookup NU author(s): Dr Kirsty Hodgson, Dr Ed Schwalbe, Dr Jonathan Coxhead, Naomi Sinclair, Dr Simon CockellORCiD, Dr Akhtar Husain, Professor Neil RajanORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 metadata

Author(s): Davies HR, Hodgson K, Schwalbe E, Coxhead J, Sinclair N, Zou X, Cockell S, Husain A, Nik-Zainal S, Rajan N

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2019

Volume: 10

Online publication date: 17/10/2019

Acceptance date: 23/09/2019

Date deposited: 14/10/2019

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/s41467-019-12746-w


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Funder referenceFunder name
Wellcome Trust