Abstract 2973: Exome sequencing of 243 liver tumors identifies new mutational signatures and potential therapeutic targets
Authors: Schulze Kornelius , Imbeaud Sandrine , Letouzé Eric , Alexandrov Ludmil B. , Calderaro Julien , Rebouissou Sandra , Couchy Gabrielle , Meiller Clément , Shinde Jayendra , Datta Shalini , Soysouvanh Frederic , Calatayud Anna-Line , Pinyol Roser , Pelletier Laura , Balabaud Charles , Laurent Alexis , Blanc Jean-Frederic , Mazzaferro Viccenzo , Calvo Fabien , Villanueva Augusto , Nault Jean-Charles , Bioulac-Sage Paulette , Stratton Michael R. , Llovet Josep M. , Zucman-Rossi Jessica 
Published: August 2015

Abstract
Background and Aims: Hepatocellular carcinoma (HCC) is a heterogeneous disease mainly developing in chronic liver disease and caused be a variety of etiologies. Hepatocarcinogenesis is a multi-step process in which pre-cancerous lesions can ultimately transform into advanced liver cancer. Genomic analyses promise to unravel the mutagenic processes in order to identify molecular profiles and to optimize personalized patient care.
Methods: We performed exome sequences of 243 liver tumors from European patients (France, Italy and Spain), associated with cirrhosis (F4, n = 118), fibrosis (F2+F3, n = 46), or non-fibrotic livers (F0+F1, n = 79). Cirrhosis-associated tumors presented different stages along HCC progression: 7 dysplastic macronodules, 7 early, 17 small and progressed, 58 classic, and 29 poor-prognosis HCC. Tumors were categorized by varying risk factors: Significant alcohol intake (41%), HCV (26%), non-alcoholic steatohepatitis (18%), HBV (14%), hemochromatosis (7%), no known etiology (11%).
Results: We identified 8 mutational signatures of which 6 (Signatures 1A, 1B, 4, 5, 6, and 16) were previously validated in a pan-cancer analysis, while 2 (Signatures 23 and 24) are novel. Hierarchical clustering, based on mutational signatures, revealed 6 groups (MSig1 to 6) and 4 singletons which were significantly associated with specific risk factors, mainly combined alcohol/tobacco consumption, and aflatoxin B1. Next, we identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes centered on CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF/CCND1 amplification, TP53 and CDKN2A alterations, appeared at more advanced stages in aggressive tumors. Altogether, 28% of patients harbored at least one damaging alteration potentially targetable by an FDA-approved drug and 86% by a drug which has been studied in phase I to phase III clinical trials.
Conclusions: In conclusion, our study identified relationships between environmental exposures and mutational patterns in HCC as well as the landscape of driver genes and pathways altered in different clinical stages and etiological backgrounds. For patient care, genomic alterations identified in targetable genes will be useful to determine HCC patients that could potentially benefit from targeted treatment in future clinical trials.
Citation Format: Kornelius Schulze, Sandrine Imbeaud, Eric Letouzé, Ludmil B. Alexandrov, Julien Calderaro, Sandra Rebouissou, Gabrielle Couchy, Clément Meiller, Jayendra Shinde, Shalini Datta, Frederic Soysouvanh, Anna-Line Calatayud, Roser Pinyol, Laura Pelletier, Charles Balabaud, Alexis Laurent, Jean-Frederic Blanc, Viccenzo Mazzaferro, Fabien Calvo, Augusto Villanueva, Jean-Charles Nault, Paulette Bioulac-Sage, Michael R. Stratton, Josep M. Llovet, Jessica Zucman-Rossi. Exome sequencing of 243 liver tumors identifies new mutational signatures and potential therapeutic targets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2973. doi:10.1158/1538-7445.AM2015-2973