Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12746-w
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Funding
- Wellcome Trust [WT097163MA]
- Newcastle NIHR Biomedical Research Center (BRC)
- Newcastle MRC/EPSRC Molecular Pathology Node
- British Skin Foundation
- CRUK Grand Challenge Award [C60100/A25274]
- CRUK Advanced Clinician Scientist Award [C60100/A23916]
- Wellcome-Beit Award
- Wellcome Strategic Award [101126/Z/13/Z]
- Josef Steiner Award 2019
- Wellcome Trust [101126/Z/13/Z] Funding Source: Wellcome Trust
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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.
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