Cutaneous cylindroma is an adnexal tumour with apocrine differentiation. A predisposition to multiple cylindromas is seen in patients with Brooke-Spiegler syndrome, who carry germline mutations in the tumour suppressor gene CYLD. Previous studies of inherited cylindromas have highlighted the frequent presence of bi-allelic truncating CYLD mutations as a recurrent driver mutation. We have previously shown that sporadic cylindromas express either MYB-NFIB fusion transcripts or show evidence of MYB activation in the absence of such fusions. Here, we investigated inherited cylindromas from several families with germline CYLD mutations for the presence of MYB activation. Strikingly, none of the inherited CYLD-defective (n = 23) tumours expressed MYB-NFIB fusion transcripts. However, MYB expression was increased in the majority of tumours (69%) and global gene expression analysis revealed that well-established MYB target genes were up-regulated in CYLD-defective tumours. Moreover, knock-down of MYB expression caused a significant reduction in cylindroma cell proliferation, suggesting that MYB is also a key player and oncogenic driver in inherited cylindromas. Taken together, our findings suggest molecular heterogeneity in the pathogenesis of sporadic and inherited cutaneous cylindromas, with convergence on MYB activation. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

• Keywords
• CYLD, MYB, MYB-NFIB, adenoid cystic carcinoma, cylindroma, gene fusion, germline mutation,
• MeSH
• Neoplastic Syndromes, Hereditary genetics   metabolism   pathology   MeSH
• Deubiquitinating Enzyme CYLD MeSH
• Adult MeSH
• Phenotype MeSH
• Oncogene Proteins, Fusion genetics   metabolism   MeSH
• Genotype MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Suppressor Proteins genetics   metabolism   MeSH
• Skin Neoplasms genetics   metabolism   pathology   MeSH
• Cell Proliferation MeSH
• Sequence Analysis, DNA MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Gene Expression Profiling MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CYLD protein, human MeSH Browser
• Deubiquitinating Enzyme CYLD MeSH
• Oncogene Proteins, Fusion MeSH
• MYB-NFIB fusion protein, human MeSH Browser
• Tumor Suppressor Proteins MeSH

Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms most commonly spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. Multiple familial trichoepithelioma (MFT) is a phenotypic variant of the disease characterized by the development of numerous trichoepitheliomas (cribriform trichoblastoma) only. Malignant tumors arise in association with preexisting benign cutaneous neoplasms in about 5-10% of the patients . Apart from the skin, major and minor salivary glands have been rarely involved in BSS patients. Extremely rare is the occurrence of breast tumors (cylindroma). The gene implicated in the pathogenesis of the disease is the CYLD gene, a tumor suppressor gene located on chromosome 16q12-q13. Germline CYLD mutations are detected in about 80-85% of patients with the classical BSS phenotype and in about 40-50% of the individuals with the MFT phenotype using a PCR based approach with analysis of exonic sequences and exon-intron junctions of the CYLD gene. There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions.

• Keywords
• Brooke-Spiegler syndrome, CYLD gene, Cylindroma, Spiradenoma, Trichoepithelioma,
• MeSH
• Neoplastic Syndromes, Hereditary * genetics   pathology   MeSH
• Deubiquitinating Enzyme CYLD MeSH
• Phenotype MeSH
• Genotype MeSH
• Humans MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Skin Neoplasms * genetics   pathology   MeSH
• Germ-Line Mutation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• CYLD protein, human MeSH Browser
• Deubiquitinating Enzyme CYLD MeSH
• Tumor Suppressor Proteins MeSH

BACKGROUND: Multiple familial trichoepithelioma type 1 (MFT1; MIM 601606), a rare monogenic skin disease with autosomal dominant inheritance, is characterized by the development of multiple skin-colored papules on the central area of the face, frequently occurring in the nasolabial area. The disease is associated with various mutations in the cylindromatosis (CYLD; MIM 605018) gene that are also responsible for familial cylindromatosis (FC) and Brooke-Spiegler syndrome (BSS). METHODS: Recently we have identified a Spanish MFT1 pedigree with two affected family members (father and daughter). Direct sequencing of the CYLD gene revealed a worldwide recurrent heterozygous nonsense mutation (c.2272C/T, p.R758X) in the patients. RESULTS: This mutation has already been detected in patients with all three clinical variants - BSS, FC and MFT1 - of the CYLD-mutation spectrum. Haplotype analysis was performed for the Spanish patients with MFT1, Dutch patients with FC and an Austrian patient with BSS, all of whom carry the same heterozygous nonsense p.R758X CYLD mutation. CONCLUSIONS: Our results indicate that this position is a mutational hotspot on the gene and that patients carrying the mutation exhibit high phenotypic diversity.

• MeSH
• Neoplastic Syndromes, Hereditary diagnosis   genetics   MeSH
• Deubiquitinating Enzyme CYLD MeSH
• Phenotype MeSH
• Haplotypes MeSH
• Heterozygote MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Skin Neoplasms diagnosis   genetics   MeSH
• Codon, Nonsense * MeSH
• Pedigree MeSH
• Sequence Analysis, DNA MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Netherlands MeSH
• Austria MeSH
• Spain MeSH
• Names of Substances
• CYLD protein, human MeSH Browser
• Deubiquitinating Enzyme CYLD MeSH
• Tumor Suppressor Proteins MeSH
• Codon, Nonsense * MeSH