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 (US)
Article number	6087
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7087
State	Published - Jan 22 2015
Externally published	Yes

ASJC Scopus subject areas

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

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10.1038/ncomms7087

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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

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

@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.}",

note = "Funding Information: This work was supported by the ILCA-Bayer Fellowship Program. We would like to thank Professor Amaia Lujambio from the Oncological Science Department for her suggestions, our lab manager Genis Camprecios and Issa K. Leonard from the Citoge-netics Laboratory for their generous help. Library preparation and sequencing was performed by the staff of the Genomics Core Facility, Icahn Institute for Genomics and Multiscale Biology at the Icahn School of Medicine at Mount Sinai. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. D.S. has been supported by fellowships from AECC (Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer), AIRC (Italian Association for Cancer Research) and ILCA (International Liver Cancer Association). A.M. is supported by a fellowship from Spanish National Health Institute (FPI program, BES-2011-046915). Y.H. is supported by grants from the National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099558), the European Commission Framework Program 7 (HEP-TROMIC, proposal number 259744). H.C. is supported by a fellowship from Instituto de Salud Carlos III (ISCIII/FIS FI10/00143). R.P. is supported by a fellowship from AECC (Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer). V.M. is supported by grants from AIRC and the Oncology Research Project of the Italian Ministry of Health. J.M.L. is supported by grants from the European Commission Framework Programme7 (Heptromic, proposal number 259744), the Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (AECC), Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (SAF2013-41027). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jan,

day = "22",

doi = "10.1038/ncomms7087",

language = "English (US)",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

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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.

N1 - Funding Information: This work was supported by the ILCA-Bayer Fellowship Program. We would like to thank Professor Amaia Lujambio from the Oncological Science Department for her suggestions, our lab manager Genis Camprecios and Issa K. Leonard from the Citoge-netics Laboratory for their generous help. Library preparation and sequencing was performed by the staff of the Genomics Core Facility, Icahn Institute for Genomics and Multiscale Biology at the Icahn School of Medicine at Mount Sinai. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. D.S. has been supported by fellowships from AECC (Asociación Española Contra el Cáncer), AIRC (Italian Association for Cancer Research) and ILCA (International Liver Cancer Association). A.M. is supported by a fellowship from Spanish National Health Institute (FPI program, BES-2011-046915). Y.H. is supported by grants from the National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099558), the European Commission Framework Program 7 (HEP-TROMIC, proposal number 259744). H.C. is supported by a fellowship from Instituto de Salud Carlos III (ISCIII/FIS FI10/00143). R.P. is supported by a fellowship from AECC (Asociación Española Contra el Cáncer). V.M. is supported by grants from AIRC and the Oncology Research Project of the Italian Ministry of Health. J.M.L. is supported by grants from the European Commission Framework Programme7 (Heptromic, proposal number 259744), the Asociación Española Contra el Cáncer (AECC), Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (SAF2013-41027). Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

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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JO - Nature communications

JF - Nature communications

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ER -

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

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