title: Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis.
abstract: Merkel cell carcinoma (MCC) is a clinically aggressive neuroendocrine skin cancer; 80% of the cases are associated with the Merkel cell polyomavirus (MCPyV). We previously reported that MCPyV-negative MCCs have more irregular nuclei with abundant cytoplasm and significantly unfavorable outcomes than do MCPyV-positive MCCs. These results suggest that some cell adhesion or structural stabilization molecules are differently expressed depending on MCPyV infection status. Thus, we investigated the association of prognosis or MCPyV infection status in MCCs with cell adhesion molecule 1 (CADM1)/differentially expressed in adenocarcinoma of the lung protein 1 (DAL-1)/membrane protein, palmitoylated 3 (MPP3) tripartite complex and mal T-cell differentiation protein (MAL) expression, which play important roles in cell adhesion and oncogenesis and are related to cancer outcomes in various malignancies, to elucidate the role of these molecules. We analyzed the pathological and molecular characteristics of 26 MCPyV-positive and 15 MCPyV-negative MCCs. Univariate Cox regression analysis showed that advanced age (hazard ratio [HR], 8.249; P = .007) and high CADM1 expression (HR, 5.214; P = .012) were significantly unfavorable overall survival parameters, whereas MCPyV infection (HR, 0.043, P < .001) and lower MAL expression (HR, 0.273; P = .018) were significantly favorable. On multivariate analysis, only MCPyV infection was significantly favorable for overall survival (HR, 0.04; P = .005). Hypermethylation of CADM1, DAL-1, and MAL promoters was detected in 1 of 18, 15 of 27, and 1 of 13 cases, respectively. Double immunostaining for cytokeratin 20 and CADM1, DAL-1, or MAL showed that nonneoplastic Merkel cells expressed DAL-1 and MAL but not CADM1. This study revealed that MCPyV-negative MCCs significantly expressed higher CADM1 and lower MAL than MCPyV-positive MCCs; these expression levels were markedly related to unfavorable outcomes. These data will give us important insights to develop novel molecular target therapies for MCCs.
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: iwasakit-path@umin.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan; Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Department of Histopathology, the Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nonaka
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwamoto
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Murakami
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan. Electronic address: hayashik@med.tottori-u.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D015266:Carcinoma, Merkel Cell / Q000401:mortality / Q000473:pathology / Q000821:virology*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D059965:Merkel cell polyomavirus; D008875:Middle Aged; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000096:biosynthesis; D027601:Polyomavirus Infections / Q000150:complications*; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000401:mortality / Q000473:pathology / Q000821:virology*; D014412:Tumor Virus Infections / Q000150:complications*
chemical_list: D014408:Biomarkers, Tumor; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins
keywords: Cell adhesion molecule 1; Differentially expressed in adenocarcinoma of the lung protein 1; Merkel cell carcinoma; Merkel cell polyomavirus; Myelin and lymphocyte protein