Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma (original) (raw)
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.
Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma / D. Sia, B. Losic, A. Moeini, L. Cabellos, K. Hao, K. Revill, D. Bonal, O. Miltiadous, Z. Zhang, Y. Hoshida, H. Cornella, M. Castillo Martin, R. Pinyol, Y. Kasai, S. Roayaie, S.N. Thung, J. Fuster, M.E. Schwartz, S. Waxman, C. Cordon Cardo, E. Schadt, V. Mazzaferro, J.M. Llovet. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 6(2015 Jan), pp. 60987.1-60987.11. [10.1038/ncomms7087]
Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
D. Sia;B. Losic;A. Moeini;L. Cabellos;K. Hao;K. Revill;D. Bonal;O. Miltiadous;Z. Zhang;Y. Hoshida;H. Cornella;M. Castillo Martin;R. Pinyol;Y. Kasai;S. Roayaie;S. N. Thung;J. Fuster;M. E. Schwartz;S. Waxman;C. Cordon Cardo;E. Schadt;;J. M. Llovet
2015
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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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/466290
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