TY - JOUR
T1 - Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups
AU - Simbolo, Michele
AU - Fassan, Matteo
AU - Ruzzenente, Andrea
AU - Mafficini, Andrea
AU - Wood, Laura D.
AU - Corbo, Vincenzo
AU - Melisi, Davide
AU - Malleo, Giuseppe
AU - Vicentini, Caterina
AU - Malpeli, Giorgio
AU - Antonello, Davide
AU - Sperandio, Nicola
AU - Capelli, Paola
AU - Tomezzoli, Anna
AU - Iacono, Calogero
AU - Lawlor, Rita T.
AU - Bassi, Claudio
AU - Hruban, Ralph H.
AU - Guglielmi, Alfredo
AU - Tortora, Giampaolo
AU - de Braud, Filippo
AU - Scarpa, Aldo
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Cholangiocarcinoma
KW - Molecular subclassification
KW - Multigene mutational panels
KW - Next-generation sequencing
KW - Target therapy
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U2 - 10.18632/oncotarget.1943
DO - 10.18632/oncotarget.1943
M3 - Article
C2 - 24867389
AN - SCOPUS:84901191451
SN - 1949-2553
VL - 5
SP - 2839
EP - 2852
JO - Oncotarget
JF - Oncotarget
IS - 9
ER -