Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome.
Nik-Zainal Abidin, Serena
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Davies, H., Hodgson, K., Schwalbe, E., Coxhead, J., Sinclair, N., Zou, X., Cockell, S., et al. (2019). Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome.. Nature communications, 10 (1), 4717. https://doi.org/10.1038/s41467-019-12746-w
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.
Humans, Skin Neoplasms, Neoplastic Syndromes, Hereditary, Proto-Oncogene Proteins, Repressor Proteins, Retrospective Studies, Gene Expression Profiling, Pedigree, DNA Mutational Analysis, DNA Methylation, Epigenesis, Genetic, Mutation, Female, Male, Whole Exome Sequencing, Deubiquitinating Enzyme CYLD, DNA (Cytosine-5-)-Methyltransferases
N.R.’s work was supported by a Wellcome Trust funded Intermediate Clinical Fellowship-WT097163MA. N.R.’s research is also supported by the Newcastle NIHR Biomedical Research Center (BRC) and the Newcastle MRC/EPSRC Molecular Pathology Node. K.H. is supported by a Ph.D. studentship from the British Skin Foundation. H.R.D. is funded by a CRUK Grand Challenge Award (C60100/A25274) and S.N.-Z. is funded by a CRUK Advanced Clinician Scientist Award (C60100/A23916). S.N.-Z.’s research is also funded by a Wellcome-Beit Award, Wellcome Strategic Award (101126/Z/13/Z), CRUK Grand Challenge Award (C60100/A25274), and Josef Steiner Award 2019.
Cancer Research UK (23916)
Wellcome Trust (101126/Z/13/Z)
External DOI: https://doi.org/10.1038/s41467-019-12746-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298781
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/