High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection

Mariette Labots, Tineke E Buffart, Josien C Haan, Nicole C T van Grieken, Marianne Tijssen, Cornelis J H van de Velde, Heike I Grabsch, Bauke Ylstra, Beatriz Carvalho, Remond J A Fijneman, Henk M W Verheul, Gerrit A Meijer

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE: 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.

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)41-52
Number of pages12
JournalCellular oncology
Volume37
Issue number1
DOIs
Publication statusPublished - Feb 2014

Keywords

  • Antineoplastic Agents
  • Cluster Analysis
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • DNA, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • Molecular Targeted Therapy
  • Reproducibility of Results
  • Stomach Neoplasms
  • Transcriptome

Cite this

Labots, M., Buffart, T. E., Haan, J. C., van Grieken, N. C. T., Tijssen, M., van de Velde, C. J. H., Grabsch, H. I., Ylstra, B., Carvalho, B., Fijneman, R. J. A., Verheul, H. M. W., & Meijer, G. A. (2014). High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection. Cellular oncology, 37(1), 41-52. https://doi.org/10.1007/s13402-013-0162-4