Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

Authors

  • Tuan Zea Tan,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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    • These authors contributing equally to this work.
  • Qing Hao Miow,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
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    • These authors contributing equally to this work.
  • Ruby Yun-Ju Huang,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. Department of Obstetrics and Gynecology, National University Health System, Singapore
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    • These authors contributing equally to this work.
  • Meng Kang Wong,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Jieru Ye,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Jieying Amelia Lau,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Meng Chu Wu,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Luqman Hakim Bin Abdul Hadi,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Richie Soong,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Mahesh Choolani,

    1. Department of Obstetrics and Gynecology, National University Health System, Singapore
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  • Ben Davidson,

    1. Division of Pathology, Norwegian Radium Hospital Oslo University Hospital, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Institute of Clinical Medicine, Oslo, Norway
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  • Jahn M. Nesland,

    1. Division of Pathology, Norwegian Radium Hospital Oslo University Hospital, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Institute of Clinical Medicine, Oslo, Norway
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  • Ling-Zhi Wang,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. Department of Pharmacology, National University of Singapore, Singapore
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  • Noriomi Matsumura,

    1. Department of Obstetrics and Gynecology, Kyoto University, Kyoto, Japan
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  • Masaki Mandai,

    1. Department of Obstetrics and Gynecology, Kyoto University, Kyoto, Japan
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  • Ikuo Konishi,

    1. Department of Obstetrics and Gynecology, Kyoto University, Kyoto, Japan
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  • Boon-Cher Goh,

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. Department of Pharmacology, National University of Singapore, Singapore
    3. Department of Hematology and Oncology, National University Health System, Singapore
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  • Jeffrey T. Chang,

    1. Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, TX, USA
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  • Jean Paul Thiery,

    Corresponding author
    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore
    3. Department of Biochemistry, National University of Singapore, Singapore
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  • Seiichi Mori

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. Department of Biochemistry, National University of Singapore, Singapore
    3. Division of Cancer Genomics, Cancer Institute of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan
    4. Present Address: Division of Cancer Genomics, Cancer Institute of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan
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Abstract

Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi-A, Epi-B, Mes, Stem-A and Stem-B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype-specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor-prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule-related processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients.

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