title: Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Rajan
authors.affiliation: Sahlgrenska Cancer Centre, Department of Pathology, University of Gothenburg, Sweden.
authors.forename: Mattias K
authors.initials: MK
authors.lastname: Andersson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sinclair
authors.affiliation: Sahlgrenska Cancer Centre, Department of Pathology, University of Gothenburg, Sweden.
authors.forename: André
authors.initials: A
authors.lastname: Fehr
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Hodgson
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: Sikl's Department of Pathology, Charles University in Prague, Medical Faculty in Pilsen, Czech Republic.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kazakov
authors.affiliation: Sikl's Department of Pathology, Charles University in Prague, Medical Faculty in Pilsen, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanecek
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Sahlgrenska Cancer Centre, Department of Pathology, University of Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C545202:MYB-NFIB fusion protein, human; D015514:Oncogene Proteins, Fusion; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: CYLD; MYB; MYB-NFIB; adenoid cystic carcinoma; cylindroma; gene fusion; germline mutation