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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2351-2357. Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-07-2356. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2356v1 103/6/2351    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sánchez-Aguilera, A. Articles by García, J. F. Search for Related Content PubMed PubMed Citation Articles by Sánchez-Aguilera, A. Articles by García, J. F. Related Collections Neoplasia Cell Cycle Oncogenes and Tumor Suppressors Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Silencing of the p18INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas Abel Sánchez-Aguilera, Julio Delgado, Francisca I. Camacho, Margarita Sánchez-Beato, Lydia Sánchez, Carlos Montalbán, Manuel F. Fresno, Carmen Martín, Miguel A. Piris, and Juan F. García From the Lymphoma Group, Molecular Pathology Program, and the Immunohistochemistry and Histology Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; the Department of Hematology, Hospital La Paz, Madrid, Spain; the Department of Internal Medicine, Hospital Ramón y Cajal, Madrid, Spain; the Department of Pathology, Hospital Central de Asturias, Oviedo, Spain; and the Department of Pathology, Hospital U. C. San Carlos, Madrid, Spain. p18INK4c is a cyclin-dependent kinase (CDK) inhibitor that interferes with the Rb-kinase activity of CDK6/CDK4. Disruption of p18INK4c in mice impairs B-cell terminal differentiation and confers increased susceptibility to tumor development; however, alterations of p18INK4c in human tumors have rarely been described. We used a tissue-microarray approach to analyze p18INK4c expression in 316 Hodgkin lymphomas (HLs). Nearly half of the HL cases showed absence of p18INK4c protein expression by Reed-Sternberg (RS) cells, in contrast with the regular expression of p18INK4c in normal germinal center cells. To investigate the cause of p18INK4c repression in RS cells, the methylation status of the p18INK4c promoter was analyzed by methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing. Hypermethylation of the p18INK4c promoter was detected in 2 of 4 HL-derived cell lines, but in none of 7 non-Hodgkin lymphoma (NHL)–derived cell lines. We also detected p18INK4c hypermethylation, associated with absence of protein expression, in 5 of 26 HL tumors. The correlation of p18INK4c immunostaining with the follow-up of the patients showed shorter overall survival in negative cases, independent of the International Prognostic Score. These findings suggest that p18INK4c may function as a tumor suppressor gene in HL, and its inactivation may contribute to the cell cycle deregulation and defective terminal differentiation characteristic of the RS cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. E. Leone, B. A. Walker, M. W. Jenner, L. Chiecchio, G. Dagrada, R. K.M. Protheroe, D. C. Johnson, N. J. Dickens, J. L. Brito, M. Else, et al. Deletions of CDKN2C in Multiple Myeloma: Biological and Clinical Implications Clin. Cancer Res., October 1, 2008; 14(19): 6033 - 6041. [Abstract] [Full Text] [PDF] X.-H. Pei, F. Bai, M. D. Smith, and Y. 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