Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
复制标题
DOI：
10.1038/ncomms7087
复制
发表时间：
2015-01-01
影响因子：
16.6
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
--
作者：
Sia, Daniela;Losic, Bojan;Llovet, Josep M.
肝内胆管癌（iCCA）是一种致命的胆管癌，预后差，治疗选择有限。通过进行RNA和外显子组测序分析，我们报告了一种新的融合事件，FGFR 2-PPHLN 1（16%），以及ARAF癌基因的破坏性突变（11%）。在这里，我们证明了染色体易位t（10; 12）（q26; q12）导致FGFR 2-PPHLN 1融合具有转化和致癌活性，这是成功地抑制了选择性FGFR 2抑制剂在体外。在ARAF突变中，N217 I和G322 S导致该通路的激活，N217 I在体外显示致癌潜力。对107例iCCA患者的队列进行筛选，结果显示FGFR 2融合是最常复发的靶向改变（45%，17/107），而它们很少出现在其他原发性肝脏肿瘤中（0/100的肝细胞癌（HCC）; 1/21的混合iCCA-HCC）。总的来说，约70%的iCCA患者具有至少一种适于治疗靶向的可操作分子改变（FGFR 2融合、IDH 1/2、ARAF、KRAS、BRAF和FGF 19）。
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.