Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors

Gastroenterology. 2012 Apr;142(4):1021-1031.e15. doi: 10.1053/j.gastro.2011.12.005. Epub 2011 Dec 13.

Abstract

Background & aims: Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%-10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy.

Methods: We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib.

Results: Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; χ(2) = 11.61; P < .0007), time to recurrence (13.7 vs 22.7 months; P < .001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGI-IV; χ(2) = 8.34; P < .03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab.

Conclusions: We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.

Publication types

  • Meta-Analysis
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Belgium
  • Bile Duct Neoplasms / drug therapy
  • Bile Duct Neoplasms / enzymology
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / mortality
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic* / enzymology
  • Bile Ducts, Intrahepatic* / pathology
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chi-Square Distribution
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / enzymology
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / mortality
  • Cholangiocarcinoma / pathology
  • Cluster Analysis
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • Female
  • Gene Expression Profiling / methods
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lapatinib
  • Laser Capture Microdissection
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Patient Selection
  • Phenotype
  • Precision Medicine
  • Prognosis
  • Proportional Hazards Models
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / analysis
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Queensland
  • Quinazolines / pharmacology
  • Risk Assessment
  • Risk Factors
  • Survival Rate
  • Time Factors
  • Trastuzumab
  • Tumor Microenvironment
  • United States
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinazolines
  • Lapatinib
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Trastuzumab