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

Daniela Sia, Bojan Losic, Agrin Moeini, Laia Cabellos, Ke Hao, Kate Revill, Dennis Bonal, Oriana Miltiadous, Zhongyang Zhang, Yujin Hoshida, Helena Cornella, Mireia Castillo-Martin, Roser Pinyol, Yumi Kasai, Sasan Roayaie, Swan N. Thung, Josep Fuster, Myron E. Schwartz, Samuel Waxman, Carlos Cordon-CardoEric Schadt, Vincenzo Mazzaferro, Josep M. Llovet

Research output: Contribution to journalArticle

130 Scopus citations

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.

Original languageEnglish (US)
Article number6087
JournalNature communications
Volume6
DOIs
StatePublished - Jan 22 2015
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Sia, D., Losic, B., Moeini, A., Cabellos, L., Hao, K., Revill, K., Bonal, D., Miltiadous, O., Zhang, Z., Hoshida, Y., Cornella, H., Castillo-Martin, M., Pinyol, R., Kasai, Y., Roayaie, S., Thung, S. N., Fuster, J., Schwartz, M. E., Waxman, S., ... Llovet, J. M. (2015). Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nature communications, 6, [6087]. https://doi.org/10.1038/ncomms7087