Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma

• Published in: Human pathology Vol. 69; pp. 8 - 14
• Main Authors: Kuromi, Teruyuki, MT, Matsushita, Michiko, CT, PhD, Iwasaki, Takeshi, MD, Nonaka, Daisuke, MD, PhD, Kuwamoto, Satoshi, MD, PhD, Nagata, Keiko, MD, PhD, Kato, Masako, MD, PhD, Akizuki, Gen, Kitamura, Yukisato, MD, PhD, Hayashi, Kazuhiko, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2017; Elsevier Limited
• Subjects: Biomarkers, Tumor - genetics; Carcinoma, Merkel Cell - chemistry; Carcinoma, Merkel Cell - genetics; Carcinoma, Merkel Cell - pathology; Carcinoma, Merkel Cell - virology; Cell Transformation, Viral; DNA Mutational Analysis; Exons; Female; GLI proteins; Hedgehog Proteins - analysis; Hedgehog Proteins - genetics; Hedgehog signal; Humans; Immunohistochemistry; Indian hedgehog (IHH); Kaplan-Meier Estimate; Male; Medical research; Merkel cell carcinoma; Merkel cell polyomavirus; Merkel cell polyomavirus - isolation & purification; Mutation; Patched1 (PTCH1); Pathology; Prognosis; Risk Factors; Signal Transduction; Silent Mutation; Skin cancer; Skin Neoplasms - chemistry; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Skin Neoplasms - virology; Smoothened (SMO); Sonic hedgehog (SHH); Studies; Tumors; Zinc Finger Protein GLI1 - analysis; Zinc Finger Protein GLI1 - genetics; United Kingdom > UK; Sonic hedgehog (SHH); GLI proteins; Merkel cell carcinoma; Patched1 (PTCH1); Smoothened (SMO); Hedgehog signal; Merkel cell polyomavirus; Indian hedgehog (IHH)
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2017.05.011

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.