Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma.
AffiliationDivision of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan
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AbstractMerkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that mostly occurs in the elderly. Merkel cell polyomavirus (MCPyV) is detected in approximately 80% of MCCs and is associated with carcinogenesis. Hedgehog signaling pathway plays a role in human embryogenesis and organogenesis. In addition, reactivation of this pathway later in life can cause tumors. 29 MCPyV-positive and 21 MCPyV-negative MCCs were immunohistochemically stained with primary antibodies for hedgehog signaling (SHH, IHH, PTCH1, SMO, GLI1, GLI2, and GLI3) and evaluated using H-score. PCR and sequence analysis for SHH and GLI1 exons were also performed. Expression of SHH was higher in MCPyV-positive MCCs than in MCPyV-negative MCCs (P<.001). Higher expression of GLI1, MCPyV-infection, male, and Japanese ethnicity were associated with better overall survival (P=.034, P=.001, P=.042, P=.036, respectively). Higher expression of SHH and MCPyV infection were associated with improved MCC-specific survival (P=.037, P=.002, respectively). The mutation analysis of prognosis-related GLI1 and SHH genes in our study revealed a low frequency of mutations in the 10 exons examined, except GLI1 exon 5, (18/22 cases) all having the same silent mutation of c.576G>A. Only two mutations with amino acid changes were detected in MCPyV-negative MCCs only: one missense mutation in GLI1 exon 4 and one nonsense mutation in SHH-3B. Expression of SHH and GLI1 may be useful prognostic markers of MCC because increased expression was associated with better prognosis. The high rate of c.576G>A silent mutation in GLI1 exon 5 was a feature of MCC.
CitationAssociation of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma. 2017 Hum Pathol
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