TY - JOUR
T1 - Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets
AU - Schulze, Kornelius
AU - Imbeaud, Sandrine
AU - Letouzé, Eric
AU - Alexandrov, Ludmil B.
AU - Calderaro, Julien
AU - Rebouissou, Sandra
AU - Couchy, Gabrielle
AU - Meiller, Clément
AU - Shinde, Jayendra
AU - Soysouvanh, Frederic
AU - Calatayud, Anna Line
AU - Pinyol, Roser
AU - Pelletier, Laura
AU - Balabaud, Charles
AU - Laurent, Alexis
AU - Blanc, Jean Frederic
AU - Mazzaferro, Vincenzo
AU - Calvo, Fabien
AU - Villanueva, Augusto
AU - Nault, Jean Charles
AU - Bioulac-Sage, Paulette
AU - Stratton, Michael R.
AU - Llovet, Josep M.
AU - Zucman-Rossi, Jessica
PY - 2015/5/30
Y1 - 2015/5/30
N2 - Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B 1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.
AB - Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B 1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.
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U2 - 10.1038/ng.3252
DO - 10.1038/ng.3252
M3 - Article
C2 - 25822088
AN - SCOPUS:84929129284
SN - 1061-4036
VL - 47
SP - 505
EP - 511
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -