Reference - Detail
| RRC ID | 67412 |
|---|---|
| Author | 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. |
| Title | Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. |
| Journal | Nat Commun |
| 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. |
| Volume | 6 |
| Pages | 6087 |
| Published | 2015-1-22 |
| DOI | 10.1038/ncomms7087 |
| PII | ncomms7087 |
| PMID | 25608663 |
| MeSH | 3T3 Cells Aged Amino Acid Sequence Animals Antigens, Neoplasm / genetics* Base Sequence Bile Duct Neoplasms / genetics* Cell Line, Tumor Cholangiocarcinoma / genetics* Cohort Studies Exome Exons Female High-Throughput Nucleotide Sequencing / methods* Humans In Situ Hybridization, Fluorescence Male Mice Middle Aged Molecular Sequence Data Mutation* Nuclear Proteins / genetics* Oligonucleotide Array Sequence Analysis Proto-Oncogene Proteins A-raf / genetics* Receptor, Fibroblast Growth Factor, Type 2 / genetics* Recombinant Fusion Proteins / chemistry Sequence Analysis, RNA Sequence Homology, Amino Acid Translocation, Genetic |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 178 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | HuCCT1(RCB1960) |