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

115 Citations (Scopus)

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

Fingerprint

sequencing
Cholangiocarcinoma
mutations
Fusion reactions
fusion
Mutation
cancer
Hepatocellular Carcinoma
Bile Duct Neoplasms
oncogenes
Exome
RNA Sequence Analysis
Genetic Translocation
prognosis
harbors
Ports and harbors
Oncogenes
ducts
liver
Liver

ASJC Scopus subject areas

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

Cite this

Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. / Sia, Daniela; Losic, Bojan; Moeini, Agrin; Cabellos, Laia; Hao, Ke; Revill, Kate; Bonal, Dennis; Miltiadous, Oriana; Zhang, Zhongyang; Hoshida, Yujin; Cornella, Helena; Castillo-Martin, Mireia; Pinyol, Roser; Kasai, Yumi; Roayaie, Sasan; Thung, Swan N.; Fuster, Josep; Schwartz, Myron E.; Waxman, Samuel; Cordon-Cardo, Carlos; Schadt, Eric; Mazzaferro, Vincenzo; Llovet, Josep M.

In: Nature communications, Vol. 6, 6087, 22.01.2015.

Research output: Contribution to journalArticle

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, SN, Fuster, J, Schwartz, ME, Waxman, S, Cordon-Cardo, C, Schadt, E, Mazzaferro, V & Llovet, JM 2015, 'Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma', Nature communications, vol. 6, 6087. https://doi.org/10.1038/ncomms7087
Sia, Daniela ; Losic, Bojan ; Moeini, Agrin ; Cabellos, Laia ; Hao, Ke ; Revill, Kate ; Bonal, Dennis ; Miltiadous, Oriana ; Zhang, Zhongyang ; Hoshida, Yujin ; Cornella, Helena ; Castillo-Martin, Mireia ; Pinyol, Roser ; Kasai, Yumi ; Roayaie, Sasan ; Thung, Swan N. ; Fuster, Josep ; Schwartz, Myron E. ; Waxman, Samuel ; Cordon-Cardo, Carlos ; Schadt, Eric ; Mazzaferro, Vincenzo ; Llovet, Josep M. / Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. In: Nature communications. 2015 ; Vol. 6.
@article{35b94d3c29b9409581efee98a5022421,
title = "Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma",
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.",
author = "Daniela Sia and Bojan Losic and Agrin Moeini and Laia Cabellos and Ke Hao and Kate Revill and Dennis Bonal and Oriana Miltiadous and Zhongyang Zhang and Yujin Hoshida and Helena Cornella and Mireia Castillo-Martin and Roser Pinyol and Yumi Kasai and Sasan Roayaie and Thung, {Swan N.} and Josep Fuster and Schwartz, {Myron E.} and Samuel Waxman and Carlos Cordon-Cardo and Eric Schadt and Vincenzo Mazzaferro and Llovet, {Josep M.}",
year = "2015",
month = "1",
day = "22",
doi = "10.1038/ncomms7087",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

AU - Sia, Daniela

AU - Losic, Bojan

AU - Moeini, Agrin

AU - Cabellos, Laia

AU - Hao, Ke

AU - Revill, Kate

AU - Bonal, Dennis

AU - Miltiadous, Oriana

AU - Zhang, Zhongyang

AU - Hoshida, Yujin

AU - Cornella, Helena

AU - Castillo-Martin, Mireia

AU - Pinyol, Roser

AU - Kasai, Yumi

AU - Roayaie, Sasan

AU - Thung, Swan N.

AU - Fuster, Josep

AU - Schwartz, Myron E.

AU - Waxman, Samuel

AU - Cordon-Cardo, Carlos

AU - Schadt, Eric

AU - Mazzaferro, Vincenzo

AU - Llovet, Josep M.

PY - 2015/1/22

Y1 - 2015/1/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84929292324&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929292324&partnerID=8YFLogxK

U2 - 10.1038/ncomms7087

DO - 10.1038/ncomms7087

M3 - Article

C2 - 25608663

AN - SCOPUS:84929292324

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6087

ER -