title: High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection.
abstract: OBJECTIVE
  The overall survival rate of patients with advanced gastric cancer is poor. Therefore, there is an urgent need for new treatment options for these patients. The identification of drug target genes located on DNA regions exhibiting high-level copy number gains (CNG) may be an effective approach, as has e.g. previously been shown for HER2. The aim of the present study was to identify putative drug targets in patients with gastric cancer by applying this strategy.
  
  
  METHODS
  Genome-wide array comparative genomic hybridization (array CGH) data available from 183 primary gastric cancer samples were analyzed through Ingenuity Pathway Analysis (IPA) to assess whether any established or potential anticancer drug target genes showed high-level CNG, including focal amplifications.
  
  
  RESULTS
  A total of 147 high-level gained regions were identified in the gastric cancer samples, harboring 167 genes that had previously been annotated as drug target genes. Thirty (18 %) of these genes showed high-level gains in at least 2 % of the tumors. The identified drug target genes included those for drugs known to be active in advanced (gastric) cancer, targets for targeted therapies in clinical development, as well as targets for drugs currently used for other indications but of potential interest for anticancer treatment. In addition, 12 potential drug target genes were identified, including genes involved in growth factor signaling and cell cycle regulation.
  
  
  CONCLUSIONS
  The majority of gastric cancers carried one or more high-level CNGs or focal amplifications encompassing putative drug target genes. A number of the associated drugs are currently not being considered for treatment of gastric cancer. Based on these results we hypothesize that DNA copy number profiling may be a useful tool to identify new drug targets and to guide individualized treatment strategies in patients with gastric cancer.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mariette
authors.initials: M
authors.lastname: Labots
authors.forename: Tineke E
authors.initials: TE
authors.lastname: Buffart
authors.forename: Josien C
authors.initials: JC
authors.lastname: Haan
authors.forename: Nicole C T
authors.initials: NC
authors.lastname: van Grieken
authors.forename: Marianne
authors.initials: M
authors.lastname: Tijssen
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Heike I
authors.initials: HI
authors.lastname: Grabsch
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.forename: Remond J A
authors.initials: RJ
authors.lastname: Fijneman
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D015203:Reproducibility of Results; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm