Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

By K. Schulze, S. Imbeaud, E. Letouzé, Ludmil B. Alexandrov, J. Calderaro, S. Rebouissou, G. Couchy, C. Meiller, Jayendra Shinde, F. Soysouvanh and 14 more. Nature Genetics, 2015

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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 B1. 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.

Subfields: Cancer Research, Hepatology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/74a80b30c84147b38e3c8fe39b309101a1d71194

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Citations in the corpus

Comprehensive Characterization of Cancer Driver Genes and Mutations (2018, methodology): “The consensus approach always had a greater inter-study overlap, with an average increase of 26% over only using a single tool, either MuSiC2 or MutSig2CV (Barbieri et al., 2012; Biankin et al., 2012; Nik-Zainal et al., 2016; Schulze et al., 2015; Stephens et al., 2012) (Table S3).”
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Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma (2017, neutral): “We report the Chi-square and Binomial test p values for the difference in the ratio of inactivating variation in each gene compared with the background rate of the entire cohort (Table S2B).”
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EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. (2018, background): “inhibitors (TKIs), such as high-focal amplification FGF19 or VEGFA, have a prevalence of less than 10%.(563,564) Three systemic drugs have shown survival benefits in the setting of phase III studies for advanced HCC, sorafenib and lenvatinib in first-line treatment and regorafenib in second-line.”
RNA N6‐methyladenosine methyltransferase‐like 3 promotes liver cancer progression through YTHDF2‐dependent posttranscriptional silencing of SOCS2 (2018, background): “Recent whole genomeand exome-sequencing analyses have delineated the mutational landscape of HCC and uncovered a number of novel driver mutations.((2)) Strikingly, epigenetic regulation is among the most prevalent aberrant pathways and may lead to profound gene expression changes to facilitate HCC f”