Practical considerations in screening for genetic alterations in cholangiocarcinoma

Ann Oncol. 2021 Sep;32(9):1111-1126. doi: 10.1016/j.annonc.2021.04.012. Epub 2021 Apr 28.


Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and ∼10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the United States. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient's genetic signature.

Keywords: actionable genetic alterations; cholangiocarcinoma; genomic profiling; next-generation sequencing; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bile Duct Neoplasms* / diagnosis
  • Bile Duct Neoplasms* / drug therapy
  • Bile Duct Neoplasms* / genetics
  • Bile Ducts, Intrahepatic
  • Cholangiocarcinoma* / diagnosis
  • Cholangiocarcinoma* / drug therapy
  • Cholangiocarcinoma* / genetics
  • Humans
  • Morpholines
  • Mutation
  • Pyrimidines
  • Pyrroles


  • Morpholines
  • Pyrimidines
  • Pyrroles
  • pemigatinib