An integrative analysis to identify driver genes in esophageal squamous cell carcinoma

Genta Sawada, Atsushi Niida, Hidenari Hirata, Hisateru Komatsu, Ryutaro Uchi, Teppei Shimamura, Yusuke Takahashi, Junji Kurashige, Tae Matsumura, Hiroki Ueo, Yuki Takano, Masami Ueda, Shotaro Sakimura, Yoshiaki Shinden, Hidetoshi Eguchi, Tomoya Sudo, Keishi Sugimachi, Makoto Yamasaki, Fumiaki Tanaka, Yuji TachimoriYoshiaki Kajiyama, Shoji Natsugoe, Hiromasa Fujita, Yoichi Tanaka, George Calin, Satoru Miyano, Yuichiro Doki, Masaki Mori, Koshi Mimori

研究成果: Contribution to journalArticle

11 引用 (Scopus)

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Background: Few driver genes have been well established in esophageal squamous cell carcinoma (ESCC). Identification of the genomic aberrations that contribute to changes in gene expression profiles can be used to predict driver genes. Methods: We searched for driver genes in ESCC by integrative analysis of gene expression microarray profiles and copy number data. To narrow down candidate genes, we performed survival analysis on expression data and tested the genetic vulnerability of each genes using public RNAi screening data. We confirmed the results by performing RNAi experiments and evaluating the clinical relevance of candidate genes in an independent ESCC cohort. Results: We found 10 significantly recurrent copy number alterations accompanying gene expression changes, including loci 11q13.2, 7p11.2, 3q26.33, and 17q12, which harbored CCND1, EGFR, SOX2, and ERBB2, respectively. Analysis of survival data and RNAi screening data suggested that GRB7, located on 17q12, was a driver gene in ESCC. In ESCC cell lines harboring 17q12 amplification, knockdown of GRB7 reduced the proliferation, migration, and invasion capacities of cells. Moreover, siRNA targeting GRB7 had a synergistic inhibitory effect when combined with trastuzumab, an anti-ERBB2 antibody. Survival analysis of the independent cohort also showed that high GRB7 expression was associated with poor prognosis in ESCC. Conclusion: Our integrative analysis provided important insights into ESCC pathogenesis. We identified GRB7 as a novel ESCC driver gene and potential new therapeutic target.

元の言語英語
記事番号e0139808
ジャーナルPloS one
10
発行部数10
DOI
出版物ステータス出版済み - 10 14 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Sawada, G., Niida, A., Hirata, H., Komatsu, H., Uchi, R., Shimamura, T., Takahashi, Y., Kurashige, J., Matsumura, T., Ueo, H., Takano, Y., Ueda, M., Sakimura, S., Shinden, Y., Eguchi, H., Sudo, T., Sugimachi, K., Yamasaki, M., Tanaka, F., ... Mimori, K. (2015). An integrative analysis to identify driver genes in esophageal squamous cell carcinoma. PloS one, 10(10), [e0139808]. https://doi.org/10.1371/journal.pone.0139808