title: OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.
abstract: 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.
authors.affiliation: Cancer Research UK Edinburgh Oncology Unit, University of Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh EH4 2XR, UK. grant.sellar@cancer.org.uk
authors.forename: Grant C
authors.initials: GC
authors.lastname: Sellar
authors.forename: Karen P
authors.initials: KP
authors.lastname: Watt
authors.forename: Genevieve J
authors.initials: GJ
authors.lastname: Rabiasz
authors.forename: Euan A
authors.initials: EA
authors.lastname: Stronach
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Eric P
authors.initials: EP
authors.lastname: Miller
authors.forename: Charles E
authors.initials: CE
authors.lastname: Massie
authors.forename: Jayne
authors.initials: J
authors.lastname: Miller
authors.forename: Bruno
authors.initials: B
authors.lastname: Contreras-Moreira
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
authors.forename: Iain
authors.initials: I
authors.lastname: Brown
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Williams
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bates
authors.forename: John F
authors.initials: JF
authors.lastname: Smyth
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D018899:CpG Islands; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D019656:Loss of Heterozygosity; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C059785:OPCML protein, human; C489214:Opcml protein, mouse; D012333:RNA, Messenger; D004247:DNA; D001374:Azacitidine