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      Overexpression of MYB drives proliferation of CYLD‐defective cylindroma cells†

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          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.

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          Most cited references 16

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          Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling.

          Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation. These data indicate that, depending on the external signals, Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth.
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            Whole exome sequencing of adenoid cystic carcinoma.

            Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.
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              Ubiquitin chain cleavage: CYLD at work.

              The tumor suppressor CYLD is a deubiquitylating enzyme that negatively regulates different signaling pathways by removing lysine 63-linked polyubiquitin chains from several specific substrates. In various tumor types, CYLD loss can lead to cell survival or cell proliferation. In addition to its loss due to mutations, CYLD expression can also be decreased through transcriptional and post-transcriptional regulatory mechanisms. Moreover, as epigenetic repression of CYLD can affect tumor progression in different cancer types, the activation of the CYLD promoter ensures the tight control of an inflammatory response. Recent work also shows that CYLD activity can be governed by different regulatory mechanisms including phosphorylation, thus providing another layer of control for diverse physiological processes. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Pathol
                J. Pathol
                10.1002/(ISSN)1096-9896
                PATH
                The Journal of Pathology
                John Wiley & Sons, Ltd (Chichester, UK )
                0022-3417
                1096-9896
                21 April 2016
                June 2016
                : 239
                : 2 ( doiID: 10.1002/path.2016.239.issue-2 )
                : 197-205
                Affiliations
                [ 1 ] Institute of Genetic MedicineNewcastle University Newcastle upon TyneUK
                [ 2 ] Sahlgrenska Cancer Centre, Department of PathologyUniversity of Gothenburg Sweden
                [ 3 ] Breakthrough Breast Cancer Research CentreInstitute of Cancer Research LondonUK
                [ 4 ] Sikl's Department of PathologyCharles University in Prague, Medical Faculty in Pilsen Czech Republic
                [ 5 ]UCSF Helen Diller Family Comprehensive Cancer Center San Francisco CAUSA
                Author notes
                [* ]Correspondence to: N Rajan, Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne NE1 3BZ, UK. E‐mail: neil.rajan@ 123456ncl.ac.uk
                Article
                PATH4717
                10.1002/path.4717
                4869681
                26969893
                © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 9
                Product
                Funding
                Funded by: Breakthrough Breast Cancer
                Funded by: Medical Research Council
                Funded by: Wellcome Trust
                Funded by: Swedish Cancer Society
                Funded by: BioCARE
                Categories
                Original Paper
                Original Papers
                Custom metadata
                2.0
                path4717
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:23.06.2016

                Pathology

                gene fusion, cylindroma, adenoid cystic carcinoma, germline mutation, cyld, myb, myb–nfib

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