Patients with rare germline mutations in the tumour suppressor CYLD progressively develop multiple skin tumours over their lifetime. The diverse histological patterns of hair follicle tumours seen in this syndrome suggest underlying genetic heterogeneity. 
To investigate this, we comprehensively profiled the genomic landscape of 42 benign and malignant tumours across 13 individuals in 4 multigenerational families with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) using whole genome and exome sequencing. 
We found recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of tumours, in addition to biallelic CYLD mutations.  Intra-patient and intra-tumour analysis revealed diverse DNMT3A missense mutations, supporting synergy between DNMT3A mutation and CYLD loss. To investigate mechanisms underlying this synergy, transcriptomic analysis of 22 CCS tumours was performed, highlighting DNMT3A overexpression in CCS tumours. Isoform specific analysis of RNA sequencing data revealed the short isoform, DNMT3A2, is selectively overexpressed. Integrated methylation and transcriptomic profiling of DNMT3A genotyped CCS tumours reveal that mutant DNMT3A2 drives tumourigenesis mechanistically through Wnt/ß-catenin pathway signaling. 
These findings highlight the Wnt/ß-catenin pathway as a histophenotypic modifier in skin tumour patterning and as a candidate oncogenic dependency in CCS.

DNMT3A is an epigenetic negative regulator of Wnt/ß-catenin pathway signalling in CYLD cutaneous syndrome.