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.
Highlights
Recurrent gene fusions linking the oncogene MYB and the transcription factor gene NFIB have been described in the vast majority of adenoid cystic carcinomas (ACCs) of the breast and head and neck [1,2,3]
We chose to explore the presence of MYB–NFIB fusion transcripts in tumours from patients with germline CYLD mutations, to determine whether such fusions were present at a similar frequency to that seen in sporadic cylindroma and ACC, which share histological similarities
We found that inherited cylindromas do not harbour MYB–NFIB gene fusions but instead show frequent overexpression of MYB mRNA and protein
Summary
Recurrent gene fusions linking the oncogene MYB and the transcription factor gene NFIB have been described in the vast majority of adenoid cystic carcinomas (ACCs) of the breast and head and neck [1,2,3]. Multiple cylindromas are seen in patients with Brooke–Spiegler syndrome (BSS), who carry germline mutations in the tumour suppressor gene CYLD. These patients develop cylindromas from puberty onwards, typically on the head and neck. These tumours show a striking architectural arrangement of tumour cells, namely, a cylindrical pattern similar to that seen in ACC. We chose to explore the presence of MYB–NFIB fusion transcripts in tumours from patients with germline CYLD mutations, to determine whether such fusions were present at a similar frequency to that seen in sporadic cylindroma and ACC, which share histological similarities. Our findings highlight that different tumourigenic events may converge on MYB, and that this oncoprotein represents a putative therapeutic target in sporadic and inherited cylindromas as well as in ACC
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