Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556008
Title: Unravelling cylindromas : a molecular dissection of CYLD defective tumours
Author: Rajan, Neil
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Abstract:
Patients with germline mutations in the tumour suppressor gene CYLD develop multiple cutaneous tumours on the head and neck; historically this has been termed “turban tumour” syndrome. Cylindromas and spiradenomas, hair follicle related tumours seen in this syndrome, cause significant clinical morbidity. Here we characterise the clinical phenotype of these patients, utilising tumour mapping to determine the location of tumours in mutation carriers from two large pedigrees. We demonstrate the disease often affects sites outwith the head and neck, and that androgen stimulated hair follicles are particularly vulnerable to tumour formation. The impact of this disease is severe, with 1 in 4 carriers of this gene undergoing complete scalp removal. To improve this outcome, we performed whole genome profiling of CYLD defective tumours, characterising genomic and transcriptomic changes to determine targetable signalling pathways. High resolution analysis using whole genome array based comparative genomic hybridisation and single nucleotide polymorphism analysis suggest that loss of heterozygosity at the CYLD locus may be the only change required for tumour phenotype. Gene expression profiling highlighted transcriptomic similarity between cylindromas and spiradenomas. Threedimensional reconstruction in silico from serial sections of tumours demonstrated contiguous growth between cylindromas and spiradenomas, in support of this finding. In both tumour types, dysregulated tropomyosin receptor kinase (TRK) signalling was found. Consistent with this, was the finding that TRKB and TRKC protein was overexpressed selectively in the tumour samples, demonstrated on a tissue microarray. Therapeutic utility of targeting this pathway was demonstrated by reduced viability of CYLD defective primary cell cultures in the presence of TRK inhibitors. These preliminary data support the use of TRK inhibitors as a therapeutic strategy in severely affected CYLD mutation carriers.
Supervisor: Not available Sponsor: North East Skin Research Fund ; Newcastle Hospital Trustees ; Breakthrough Breast Cancer Research ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.556008  DOI: Not available
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