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

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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.

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Acknowledgments

We thank the Mapping Core and Map Finishing groups of the Wellcome Trust Sanger Institute for initial clone supply and verification. This work was financially supported by the AEGON International Scholarship in Oncology.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Mariette Labots, Tineke E. Buffart & Henk M. W. Verheul

  2. Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

    Josien C. Haan, Nicole C. T. van Grieken, Marianne Tijssen, Bauke Ylstra, Beatriz Carvalho, Remond J. A. Fijneman & Gerrit A. Meijer

  3. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Cornelis J. H. van de Velde

  4. Department of Pathology and Tumor Biology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK

    Heike I. Grabsch

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  1. Mariette Labots
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Tineke E. Buffart and Josien C. Haan contributed equally

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Supplementary table 1

Overview of all high-level copy number gains observed in 183 gastric cancers including the chromosomal position and size (Mb). (DOCX 38 kb)

Supplementary table 2

Chromosomal start and end positions of the high-level copy number gains containing the putative drug target genes. Positions are represented according to the NCBI Build 35/hg17 and, after conversion, the GRCh37/hg19 assembly of the UCSC Genome Browser. Chr, chromosome; Start resp End, genome position in basepairs. (DOCX 24.4 kb)

Supplementary table 3

Target genes of drugs without apparent anticancer effect showing high-level copy number gain in at least 2 % of the samples. IPA, Ingenuity Pathway Analysis; DIP, Database of Interacting Proteins; NA, not applicable. (DOCX 23.4 kb)

Supplementary figure 1

Two examples of HER2 protein expression in tissue microarray cores of gastric tumors with HER2 amplification showing over-expression (40×). (DOCX 14.2 MB)

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Labots, M., Buffart, T.E., Haan, J.C. et al. High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection. Cell Oncol. 37, 41–52 (2014). https://doi.org/10.1007/s13402-013-0162-4

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