Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups
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Michele Simbolo1,2,*, Matteo Fassan1,2,*, Andrea Ruzzenente3,*, Andrea Mafficini1, Laura D. Wood4, Vincenzo Corbo1, Davide Melisi5, Giuseppe Malleo6, Caterina Vicentini1, Giorgio Malpeli1,3,6, Davide Antonello1,3,6, Nicola Sperandio1, Paola Capelli2, Anna Tomezzoli2, Calogero Iacono3, Rita T. Lawlor1,2, Claudio Bassi6, Ralph H. Hruban4, Alfredo Guglielmi3, Giampaolo Tortora5, Filippo de Braud7, Aldo Scarpa1,2
1 ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
2 Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
3 Department of Surgery, General Surgery A, University of Verona, Verona, Italy
4 Department of Pathology, Johns Hopkins University and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
5 Department of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy
6 Department of Surgery, General Surgery B, University of Verona, Verona, Italy
7 Medical Oncology Unit 1, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
* shared first authorship
Aldo Scarpa, email:
Keywords: cholangiocarcinoma; next-generation sequencing; molecular subclassification; target therapy; multigene mutational panels
Received: April 2, 2014 Accepted: April 30, 2014 Published: May 1, 2014
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.
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