OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer

• Published in: Nature genetics Vol. 34; no. 3; pp. 337 - 343
• Main Authors: Sellar, Grant C, Gabra, Hani, Watt, Karen P, Rabiasz, Genevieve J, Stronach, Euan A, Li, Li, Miller, Eric P, Massie, Charles E, Miller, Jayne, Contreras-Moreira, Bruno, Scott, Diane, Brown, Iain, Williams, Alastair R, Bates, Paul A, Smyth, John F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.07.2003
• Subjects: Animals; Azacitidine - pharmacology; Biological and medical sciences; Breast Neoplasms - genetics; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Case-Control Studies; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Chromosomes, Human, Pair 11 - genetics; Control; CpG Islands; DNA - genetics; DNA - metabolism; DNA Methylation; Enzyme Inhibitors - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Genes, Tumor Suppressor - physiology; Genetic aspects; GPI-Linked Proteins; Humans; Loss of Heterozygosity; Mice; Mice, Nude; Models, Molecular; Molecular and cellular biology; Mutagenesis, Site-Directed; Mutation - genetics; Neoplasms, Glandular and Epithelial - genetics; Nerve Tissue Proteins - genetics; Ovarian cancer; Ovarian Neoplasms - genetics; Physiological aspects; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Messenger - metabolism; Transfection; Tumor Cells, Cultured - transplantation; Tumor suppressor genes; United Kingdom; Genetics
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1183

Epithelial ovarian cancer (EOC), the leading cause of death from gynecological malignancy, is a poorly understood disease. The typically advanced presentation of EOC with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases are hallmarks of the disease. These features relate to the biology of the disease, which is a principal determinant of outcome. EOC arises as a result of genetic alterations sustained by the ovarian surface epithelium (OSE; ref. 3). The causes of these changes are unknown but are manifest by activation of oncogenes and inactivation of tumor-suppressor genes (TSGs). Our analysis of loss of heterozygosity at 11q25 identified OPCML (also called OBCAM), a member of the IgLON family of immunoglobulin (Ig) domain-containing glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecules, as a candidate TSG in EOC. OPCML is frequently somatically inactivated in EOC by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with TSG properties both in vitro and in vivo. A somatic missense mutation from an individual with EOC shows clear evidence of loss of function. These findings suggest that OPCML is an excellent candidate for the 11q25 ovarian cancer TSG. This is the first description to our knowledge of the involvement of the IgLON family in cancer.