Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

Nat Commun. 2015 Jan 22;6:6087. doi: 10.1038/ncomms7087.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Aged
  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm / genetics*
  • Base Sequence
  • Bile Duct Neoplasms / genetics*
  • Cell Line, Tumor
  • Cholangiocarcinoma / genetics*
  • Cohort Studies
  • Exome
  • Exons
  • Female
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Nuclear Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins A-raf / genetics*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Recombinant Fusion Proteins / chemistry
  • Sequence Analysis, RNA
  • Sequence Homology, Amino Acid
  • Translocation, Genetic

Substances

  • Antigens, Neoplasm
  • Nuclear Proteins
  • PPHLN1 protein, human
  • Recombinant Fusion Proteins
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • Proto-Oncogene Proteins A-raf

Associated data

  • GEO/GSE63420