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Genomics to immunotherapy of ovarian clear cell carcinoma: Unique opportunities for management

  • Author Footnotes
    1 Contributed equally to work.
    Katsutoshi Oda
    Correspondence
    Correspondence to: K. Oda, Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
    Footnotes
    1 Contributed equally to work.
    Affiliations
    Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Author Footnotes
    1 Contributed equally to work.
    Junzo Hamanishi
    Correspondence
    Correspondence to: J. Hamanishi, Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
    Footnotes
    1 Contributed equally to work.
    Affiliations
    Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Koji Matsuo
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA

    Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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  • Kosei Hasegawa
    Affiliations
    Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
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  • Author Footnotes
    1 Contributed equally to work.
Published:September 12, 2018DOI:https://doi.org/10.1016/j.ygyno.2018.09.001

      Highlights

      • OCCC is distinct from other ovarian cancers in its genetic, epigenetic, metabolomic and immunologic profile.
      • Epigenetic/metabolomic modifications contribute to cell survival against oxidative stress.
      • A unique immune microenvironment causes immune-suppressive state in OCCC.
      • Genetic, epigenetic, metabolomic and immunologic differences of OCCC can be used to design treatments specific to OCCC.

      Abstract

      Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options.

      Keywords

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