TY - JOUR
T1 - An integrative analysis to identify driver genes in esophageal squamous cell carcinoma
AU - Sawada, Genta
AU - Niida, Atsushi
AU - Hirata, Hidenari
AU - Komatsu, Hisateru
AU - Uchi, Ryutaro
AU - Shimamura, Teppei
AU - Takahashi, Yusuke
AU - Kurashige, Junji
AU - Matsumura, Tae
AU - Ueo, Hiroki
AU - Takano, Yuki
AU - Ueda, Masami
AU - Sakimura, Shotaro
AU - Shinden, Yoshiaki
AU - Eguchi, Hidetoshi
AU - Sudo, Tomoya
AU - Sugimachi, Keishi
AU - Yamasaki, Makoto
AU - Tanaka, Fumiaki
AU - Tachimori, Yuji
AU - Kajiyama, Yoshiaki
AU - Natsugoe, Shoji
AU - Fujita, Hiromasa
AU - Tanaka, Yoichi
AU - Calin, George
AU - Miyano, Satoru
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Mimori, Koshi
N1 - Publisher Copyright:
© 2015 Sawada et al.
PY - 2015/10/14
Y1 - 2015/10/14
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0139808
DO - 10.1371/journal.pone.0139808
M3 - Article
C2 - 26465158
AN - SCOPUS:84948981557
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 10
M1 - e0139808
ER -