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Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma.
Kuromi, T Matsushita, M Iwasaki, T Nonaka, Daisuke Kuwamoto, S Nagata, K Kato, M Akizuki, G Kitamura, Y Hayashi, K
Kuromi, T
Matsushita, M
Iwasaki, T
Nonaka, Daisuke
Kuwamoto, S
Nagata, K
Kato, M
Akizuki, G
Kitamura, Y
Hayashi, K
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Abstract
Merkel 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.
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Date
2017-05-24
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Article
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Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma. 2017 Hum Pathol