Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention

Clin Cancer Res. 2018 Sep 1;24(17):4154-4161. doi: 10.1158/1078-0432.CCR-18-0078. Epub 2018 May 30.


Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response.Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2 Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154-61. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / pathology
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • DNA-Binding Proteins
  • Disease-Free Survival
  • Exons / genetics
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Introns / genetics
  • Isocitrate Dehydrogenase / genetics
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics
  • Oncogene Proteins, Fusion / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptor, ErbB-2 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Young Adult


  • ARID1A protein, human
  • BAP1 protein, human
  • Biomarkers, Tumor
  • CDKN2A protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • KRAS protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • ERBB2 protein, human
  • FGFR2 protein, human
  • Receptor, ErbB-2
  • Receptor, Fibroblast Growth Factor, Type 2
  • Ubiquitin Thiolesterase
  • Proto-Oncogene Proteins p21(ras)