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.

• Klíčová slova
• Brooke-Spiegler syndrome, CYLD gene, Cylindroma, Spiradenoma, Trichoepithelioma,
• MeSH
• dědičné nádorové syndromy * genetika   patologie   MeSH
• deubikvitinizační enzym CYLD MeSH
• fenotyp MeSH
• genotyp MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory kůže * genetika   patologie   MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• CYLD protein, human MeSH Prohlížeč
• deubikvitinizační enzym CYLD MeSH
• nádorové supresorové proteiny MeSH

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.

• Klíčová slova
• CYLD, MYB, MYB-NFIB, adenoid cystic carcinoma, cylindroma, gene fusion, germline mutation,
• MeSH
• dědičné nádorové syndromy genetika   metabolismus   patologie   MeSH
• deubikvitinizační enzym CYLD MeSH
• dospělí MeSH
• fenotyp MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• genotyp MeSH
• hybridizace in situ fluorescenční MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• nádory kůže genetika   metabolismus   patologie   MeSH
• proliferace buněk MeSH
• sekvenční analýza DNA MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CYLD protein, human MeSH Prohlížeč
• deubikvitinizační enzym CYLD MeSH
• fúzní onkogenní proteiny MeSH
• MYB-NFIB fusion protein, human MeSH Prohlížeč
• nádorové supresorové proteiny 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
• dědičné nádorové syndromy diagnóza   genetika   MeSH
• deubikvitinizační enzym CYLD MeSH
• fenotyp MeSH
• haplotypy MeSH
• heterozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory kůže diagnóza   genetika   MeSH
• nesmyslný kodon * MeSH
• rodokmen MeSH
• sekvenční analýza DNA MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Nizozemsko MeSH
• Rakousko MeSH
• Španělsko MeSH
• Názvy látek
• CYLD protein, human MeSH Prohlížeč
• deubikvitinizační enzym CYLD MeSH
• nádorové supresorové proteiny MeSH
• nesmyslný kodon * MeSH