One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.
Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups / M. Simbolo, M. Fassan, A. Ruzzenente, A. Mafficini, L.D. Wood, V. Corbo, D. Melisi, G. Malleo, C. Vicentini, G. Malpeli, D. Antonello, N. Sperandio, P. Capelli, A. Tomezzoli, C. Iacono, R.T. Lawlor, C. Bassi, R.H. Hruban, A. Guglielmi, G. Tortora, F. de Braud, A. Scarpa. - In: ONCOTARGET. - ISSN 1949-2553. - 5:9(2014 May 15), pp. 2839-2852.
|Titolo:||Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups|
DE BRAUD, FILIPPO GUGLIELMO MARIA (Penultimo)
|Parole Chiave:||Aged; Bile Duct Neoplasms; Bile Ducts, Extrahepatic; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Female; Follow-Up Studies; Gallbladder Neoplasms; High-Throughput Nucleotide Sequencing; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Male; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||15-mag-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.18632/oncotarget.1943|
|Appare nelle tipologie:||01 - Articolo su periodico|