An integrative approach identified genes associated with drug response in gastric cancer

Carcinogenesis. 2015 Apr;36(4):441-51. doi: 10.1093/carcin/bgv014. Epub 2015 Mar 5.

Abstract

Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Calcium-Binding Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cisplatin / pharmacology
  • Cytoskeletal Proteins / genetics
  • DEAD-box RNA Helicases / biosynthesis
  • DEAD-box RNA Helicases / genetics*
  • DNA Copy Number Variations / genetics
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • DNA Methylation / genetics
  • Databases, Nucleic Acid
  • Drug Resistance, Neoplasm / genetics*
  • Epirubicin / pharmacology
  • Gastric Mucosa / cytology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Histones / genetics
  • Humans
  • Nerve Tissue Proteins / genetics
  • Prognosis
  • RNA Interference
  • RNA, Small Interfering
  • Retrospective Studies
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics*
  • Transcription Factors / genetics

Substances

  • Antineoplastic Agents
  • Calcium-Binding Proteins
  • Cytoskeletal Proteins
  • H2AX protein, human
  • Histones
  • NELL1 protein, human
  • Nerve Tissue Proteins
  • RAI14 protein, human
  • RNA, Small Interfering
  • Transcription Factors
  • negative elongation factor
  • Epirubicin
  • DDX27 protein, human
  • DEAD-box RNA Helicases
  • Cisplatin