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-Cardo; Eric Schadt; Vincenzo Mazzaferro; Josep M. Llovet

doi:10.1038/ncomms7087

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

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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 language	English
Article number	6087
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7087
State	Published - 22 Jan 2015

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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, Article 6087. https://doi.org/10.1038/ncomms7087

@article{613ff94f890243c0ae7ddbd731c65376,

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 = jan,

day = "22",

doi = "10.1038/ncomms7087",

language = "English",

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journal = "Nature Communications",

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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, 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

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.

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U2 - 10.1038/ncomms7087

DO - 10.1038/ncomms7087

M3 - Article

C2 - 25608663

AN - SCOPUS:84929292324

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6087

ER -

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

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