title: An Integrative Analysis to Identify Driver Genes in Esophageal Squamous Cell Carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  Our integrative analysis provided important insights into ESCC pathogenesis. We identified GRB7 as a novel ESCC driver gene and potential new therapeutic target.
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Sawada
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Hisateru
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Tae
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueo
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sakimura
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shinden
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sudo
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.affiliation: Department of Esophageal and Gastroenterological Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kajiyama
authors.affiliation: Department of Surgical Oncology and Digestive Surgery, Kagoshima University School of Medicine, Kagoshima, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Calin
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu 874-0838, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000648:ultrastructure; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D051382:GRB7 Adaptor Protein / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D034622:RNA Interference
chemical_list: C495955:GRB7 protein, human; D051382:GRB7 Adaptor Protein