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

被引：252

作者：

Sia, Daniela ^{[1
,2
,3
]}

Losic, Bojan ^{[3
,4
]}

Moeini, Agrin ^{[1
]}

Cabellos, Laia ^{[3
]}

Hao, Ke ^{[4
]}

Revill, Kate ^{[3
]}

Bonal, Dennis ^{[3
]}

Miltiadous, Oriana ^{[3
]}

Zhang, Zhongyang ^{[3
,4
]}

Hoshida, Yujin ^{[3
]}

Cornella, Helena ^{[1
]}

Castillo-Martin, Mireia ^{[3
]}

Pinyol, Roser ^{[1
]}

Kasai, Yumi ^{[4
]}

Roayaie, Sasan

Thung, Swan N. ^{[3
]}

Fuster, Josep ^{[1
]}

Schwartz, Myron E. ^{[3
]}

Waxman, Samuel ^{[3
]}

Cordon-Cardo, Carlos ^{[3
]}

Schadt, Eric ^{[4
]}

Mazzaferro, Vincenzo ^{[2
]}

Llovet, Josep M. ^{[1
,3
,5
]}

机构：

[1] Univ Barcelona, Barcelona Clin Liver Canc Grp, HCC Translat Res Lab, Liver Unit,IDIBAPS,Hosp Clin,CIBERehd, E-08036 Barcelona, Spain

[2] Natl Canc Inst, Dept Surg, Gastrointestinal Surg & Liver Transplantat Unit, I-20133 Milan, Italy

[3] Icahn Sch Med Mt Sinai, Mt Sinai Liver Canc Program, Div Liver Dis,Tisch Canc Inst, Dept Med,Dept Pathol,Recanati Miller Transplantat, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[5] Inst Catalana Recerca & Estudis Avancats, Barcelona 08010, Spain

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

芬兰科学院;

关键词：

CELL LUNG-CANCER; TARGETED THERAPY; BREAST-CANCER; GENE FUSIONS; B-RAF; IDENTIFICATION; DIFFERENTIATION; PATHOGENESIS; TRANSCRIPTS; ACTIVATION;

D O I：

10.1038/ncomms7087

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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