Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Han Liang, Lydia W.T. Cheung, Jie Li, Zhenlin Ju, Shuangxing Yu, Katherine Stemke-Hale, Turgut Dogruluk, Yiling Lu, Xiuping Liu, Chao Gu, Wei Guo, Steven E. Scherer, Hannah Carter, Shannon N. Westin, Mary D. Dyer, Roeland G.W. Verhaak, Fan Zhang, Rachel Karchin, Chang Gong Liu, Karen H. LuRussell R. Broaddus, Kenneth L. Scott, Bryan T. Hennessy, Gordon B. Mills

    Research output: Contribution to journalArticle

    158 Scopus citations

    Abstract

    Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the ''sensor'' cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.

    Original languageEnglish (US)
    Pages (from-to)2120-2129
    Number of pages10
    JournalGenome Research
    Volume22
    Issue number11
    DOIs
    StatePublished - Nov 2012

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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  • Cite this

    Liang, H., Cheung, L. W. T., Li, J., Ju, Z., Yu, S., Stemke-Hale, K., Dogruluk, T., Lu, Y., Liu, X., Gu, C., Guo, W., Scherer, S. E., Carter, H., Westin, S. N., Dyer, M. D., Verhaak, R. G. W., Zhang, F., Karchin, R., Liu, C. G., ... Mills, G. B. (2012). Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Research, 22(11), 2120-2129. https://doi.org/10.1101/gr.137596.112