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

Nature Genetics volume 34, pages 337–343 (2003)Cite this article

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 outcome1,2. 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.

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Figure 1: Loss of heterozygosity at 11q25 associated with EOC.
Figure 2: RT–PCR analysis of OPCML expression.
Figure 3: OPCML CpG island methylation.
Figure 4: OPCML has functional characteristics of a TSG in vitro.
Figure 5: OPCML has functional characteristics of a TSG in vivo.
Figure 6: OPCML P95R somatic mutation shows loss of cellular aggregation function.

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Acknowledgements

The authors thank D. Porteous and S. Kerr for use of their facilities, S. Langdon for ovarian tumor RNAs and S. Bader for cell line DNAs. K.P.W. was funded by Scottish Hospitals Endowment Research Trust and University of Edinburgh Faculty of Medicine Fellowships. L.L. was funded by a Chinese Government Fellowship.

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Author notes

  1. Li Li

    Present address: Department of Gynecologic Oncology, Guangxi Cancer Institute Affiliated Tumor Hospital, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China

Authors and Affiliations

  1. Cancer Research UK Edinburgh Oncology Unit, University of Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, EH4 2XR, UK

    Grant C Sellar, Karen P Watt, Genevieve J Rabiasz, Euan A Stronach, Li Li, Eric P Miller, Charles E Massie, Jayne Miller, Diane Scott, John F Smyth & Hani Gabra

  2. Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Bruno Contreras-Moreira & Paul A Bates

  3. Department of Surgery, University of Aberdeen Medical School, Aberdeen, AB25 2ZD, UK

    Iain Brown

  4. Department of Pathology, University of Edinburgh Medical School, Edinburgh, EH16 4SA, UK

    Alastair R Williams

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Correspondence to Grant C Sellar or Hani Gabra.

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Sellar, G., Watt, K., Rabiasz, G. et al. OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer. Nat Genet 34, 337–343 (2003). https://doi.org/10.1038/ng1183

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