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Transition from cylindroma to spiradenoma in CYLD‐defective tumours is associated with reduced DKK2 expression
Author(s) -
Rajan Neil,
Burn John,
Langtry James,
SieberBlum Maya,
Lord Christopher J,
Ashworth Alan
Publication year - 2011
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2896
Subject(s) - biology , cylindroma , wnt signaling pathway , cancer research , gene silencing , epigenetics , gene expression , germline , gene , pathology , genetics , medicine
Patients carrying heterozygous germline truncating mutations in the CYLD gene develop multiple primary hair follicle‐related tumours. A highly patterned tumour, termed cylindroma, and a highly disorganized tumour, termed spiradenoma, may both develop in the same patient. Furthermore, histological features of both tumour types have been described within the same tumour specimen. We used three‐dimensional computer‐aided reconstruction of these tumours to demonstrate contiguous growth of cylindromas into spiradenomas, thus suggesting a transition between the two tumour types. To explore factors that may influence cutaneous tumour patterning, genome‐wide transcriptomic analysis of 32 CYLD‐defective tumours was performed. Overexpression of the Wnt/β‐catenin signalling pathway was observed relative to normal perilesional tissue. Morphometric analysis was used to investigate the relationship between Wnt pathway‐related gene expression and tumour organization. This revealed an association between reduced Dickkopf 2 (DKK2—a negative regulator of the Wnt/β‐catenin signalling pathway) expression and loss of tumour patterning. Reduced DKK2 expression was associated with methylation of the DKK2 gene promoter in the majority of tumour samples assayed. RNA interference‐mediated silencing of DKK2 expression in cylindroma primary cell cultures caused an increase in colony formation, cell viability, and anchorage‐independent growth. Using these data, we propose a model where epigenetic programming may influence tumour patterning in patients with CYLD mutations. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.