Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression

• Published in: The Journal of pathology Vol. 224; no. 3; pp. 309 - 321
• Main Authors: Rajan, Neil, Burn, John, Langtry, James, Sieber-Blum, Maya, Lord, Christopher J, Ashworth, Alan
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.07.2011; Wiley
• Subjects: Adenoma, Sweat Gland - genetics; Adenoma, Sweat Gland - metabolism; Adenoma, Sweat Gland - pathology; beta Catenin - metabolism; Biological and medical sciences; Carcinoma, Adenoid Cystic - genetics; Carcinoma, Adenoid Cystic - metabolism; Carcinoma, Adenoid Cystic - pathology; Cell Proliferation; CYLD; cylindroma; Dermatology; Deubiquitinating Enzyme CYLD; Disease Progression; DKK2; DNA Methylation; DNA, Neoplasm - genetics; epigenetics; Gene Knockdown Techniques; Genome-Wide Association Study - methods; Germ-Line Mutation; Humans; Imaging, Three-Dimensional; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Neoplasm Proteins - metabolism; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Promoter Regions, Genetic; Signal Transduction; skin cancer; Skin involvement in other diseases. Miscellaneous. General aspects; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Sweat Gland Neoplasms - genetics; Sweat Gland Neoplasms - metabolism; Sweat Gland Neoplasms - pathology; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumors of the skin and soft tissue. Premalignant lesions; Wnt Proteins - metabolism; Skin disease; Deficiency; Spiradenoma eccrine; Adenoma; Malignant tumor; DKK2; Skin cancer; Cylindroma; CYLD; Anatomic pathology; Association; Epigenetics; Skin; Benign neoplasm; Cancer; Sweat gland disease
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2896

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.