Genome Wide DNA Copy Number Analysis in Cholangiocarcinoma Using High Resolution Molecular Inversion Probe Single Nucleotide Polymorphism Assay

Exp Mol Pathol. 2015 Oct;99(2):344-53. doi: 10.1016/j.yexmp.2015.08.003. Epub 2015 Aug 8.

Abstract

In order to study molecular similarities and differences of intrahepatic (IH-CCA) and extrahepatic (EH-CCA) cholangiocarcinoma, 24 FFPE tumor samples (13 IH-CCA, 11 EH-CCA) were analyzed for whole genome copy number variations (CNVs) using a new high-density Molecular Inversion Probe Single Nucleotide Polymorphism (MIP SNP) assay. Common in both tumor subtypes the most frequent losses were detected on chromosome 1p, 3p, 6q and 9 while gains were mostly seen in 1q, 8q as well as complete chromosome 17 and 20. Applying the statistical GISTIC (Genomic Identification of Significant Targets in Cancer) tool we identified potential novel candidate tumor suppressor- (DBC1, FHIT, PPP2R2A) and oncogenes (LYN, FGF19, GRB7, PTPN1) within these regions of chromosomal instability. Next to common aberrations in IH-CCA and EH-CCA, we additionally found significant differences in copy number variations on chromosome 3 and 14. Moreover, due to the fact that mutations in the Isocitrate dehydrogenase (IDH-1 and IDH-2) genes are more frequent in our IH-CCA than in our EH-CCA samples, we suggest that the tumor subtypes have a different molecular profile. In conclusion, new possible target genes within regions of high significant copy number aberrations were detected using a high-density Molecular Inversion Probe Single Nucleotide Polymorphism (MIP SNP) assay, which opens a future perspective of fast routine copy number and marker gene identification for gene targeted therapy.

Keywords: Cholangiocarcinoma; Copy number aberrations; ERBB2; IDH; Molecular inversion probe.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Extrahepatic / metabolism*
  • Bile Ducts, Extrahepatic / pathology
  • Bile Ducts, Intrahepatic / metabolism*
  • Bile Ducts, Intrahepatic / pathology
  • Biomarkers, Tumor / genetics
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / pathology
  • Chromosome Aberrations
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations*
  • Female
  • Genome, Human
  • Humans
  • Immunoenzyme Techniques
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Molecular Probes / genetics*
  • Mutation / genetics
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Biomarkers, Tumor
  • Molecular Probes
  • RNA, Messenger