Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas

Authors

  • Melissa K McConechy,

    1. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada
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    • These authors contributed equally to this study.

  • Michael S Anglesio,

    1. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada
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    • These authors contributed equally to this study.

  • Steve E Kalloger,

    1. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • Winnie Yang,

    1. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • Janine Senz,

    1. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • Christine Chow,

    1. Genetic Pathology Evaluation Centre of the Prostate Research Centre and Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada
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  • Alireza Heravi-Moussavi,

    1. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • Gregg B Morin,

    1. Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Department of Medical Genetics, University of BC, Vancouver, Canada
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  • Anne-Marie Mes-Masson,

    1. Centre de Recherche CHUM et Institut du Cancer de Montréal Hôpital Notre-Dame, Université de Montréal, Montreal, Quebec, Canada
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  • Australian Ovarian Cancer Study Group,

    1. Peter MacCallum Cancer Centre and the University of Melbourne, Victoria, Australia; Queensland Institute of Medical Research, Brisbane, Queensland, Australia; and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Sydney, Australia; Management Group, D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green and P. Webb
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  • Mark S Carey,

    1. Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada
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  • Jessica N McAlpine,

    1. Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada
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  • Janice S Kwon,

    1. Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada
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  • Leah M Prentice,

    1. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • Niki Boyd,

    1. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • Sohrab P Shah,

    1. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada
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  • C. Blake Gilks,

    1. Genetic Pathology Evaluation Centre of the Prostate Research Centre and Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada
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  • David G Huntsman

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada
    2. Genetic Pathology Evaluation Centre of the Prostate Research Centre and Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada
    • Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, Genetic Pathology Evaluation Centre of the Prostate Rearch Centre, 3427-600 West 10th Avenue, Vancouver BC V5E 4E6, Canada.
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  • No conflicts of interest were declared.

Abstract

PPP2R1A mutations have recently been described in 3/42 (7%) of clear cell carcinomas of the ovary. PPP2R1A encodes the α-isoform of the scaffolding subunit of the serine/threonine protein phosphatase 2A (PP2A) holoenzyme. This putative tumour suppressor complex is involved in growth and survival pathways. Through targeted sequencing of PPP2R1A, we identified somatic missense mutations in 40.8% (20/49) of high-grade serous endometrial tumours, and 5.0% (3/60) of endometrial endometrioid carcinomas. Mutations were also identified in ovarian tumours at lower frequencies: 12.2% (5/41) of endometrioid and 4.1% (2/49) of clear cell carcinomas. No mutations were found in 50 high-grade and 12 low-grade serous carcinomas. Amino acid residues affected by these mutations are highly conserved across species and are involved in direct interactions with regulatory B-subunits of the PP2A holoenzyme. PPP2R1A mutations in endometrial high-grade serous carcinomas are a frequent and potentially targetable feature of this disease. The finding of frequent PPP2R1A mutations in high-grade serous carcinoma of the endometrium but not in high-grade serous carcinoma of the ovary provides clear genetic evidence that these are distinct diseases. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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