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

Davies, Helen R., Hodgson, Kirsty, Schwalbe, Ed, Coxhead, Jonathan, Sinclair, Naomi, Zou, Xueqing, Cockell, Simon, Husain, Akhtar, Nik-Zainal, Serena and Rajan, Neil (2019) Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome. Nature Communications, 10 (1). ISSN 2041-1723

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Official URL: http://dx.doi.org/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.

Item Type: Article
Subjects: A300 Clinical Medicine
C400 Genetics
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Paul Burns
Date Deposited: 22 Oct 2019 09:51
Last Modified: 22 Oct 2019 10:00
URI: http://nrl.northumbria.ac.uk/id/eprint/41194

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