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. 2015 Jan 22:6:6087.
doi: 10.1038/ncomms7087.

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

Daniela Sia  1 , Bojan Losic  2 , Agrin Moeini  3 , Laia Cabellos  4 , Ke Hao  2 , Kate Revill  4 , Dennis Bonal  4 , Oriana Miltiadous  4 , Zhongyang Zhang  2 , Yujin Hoshida  4 , Helena Cornella  3 , Mireia Castillo-Martin  4 , Roser Pinyol  3 , Yumi Kasai  5 , Sasan Roayaie  6 , Swan N Thung  4 , Josep Fuster  3 , Myron E Schwartz  4 , Samuel Waxman  4 , Carlos Cordon-Cardo  4 , Eric Schadt  5 , Vincenzo Mazzaferro  7 , Josep M Llovet  8
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Free article

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

Daniela Sia et al. Nat Commun. .
Free article

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.

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