Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
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DOI：
10.1038/ng.3252
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发表时间：
2015-05
期刊：
影响因子：
30.8
通讯作者：
Zucman-Rossi J
中科院分区：
文献类型：
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作者：
Schulze K;Imbeaud S;Letouzé E;Alexandrov LB;Calderaro J;Rebouissou S;Couchy G;Meiller C;Shinde J;Soysouvanh F;Calatayud AL;Pinyol R;Pelletier L;Balabaud C;Laurent A;Blanc JF;Mazzaferro V;Calvo F;Villanueva A;Nault JC;Bioulac-Sage P;Stratton MR;Llovet JM;Zucman-Rossi J
基因组分析有望改善肿瘤特征，以优化肝细胞癌（HCC）患者的个性化治疗。对243例肝肿瘤的外显子组测序分析揭示了与特定风险因素相关的突变特征，主要是酒精/烟草消费和黄曲霉毒素B1。我们确定了161个推定的驱动基因与11个复发途径。突变的关联定义了3组与风险因素相关的基因，集中在CTNNB 1（酒精），TP 53（HBV）和AXIN 1。根据肿瘤分期进展的分析显示，TERT启动子突变是早期事件，而FGF 3、FGF 4、FGF 19/CCND 1扩增、TP 53和CDKN 2A改变出现在侵袭性肿瘤的更晚期阶段。在28%的肿瘤中，我们发现了FDA批准的药物可能靶向的遗传改变。总之，我们确定了危险因素特异性突变特征，并确定了HCC中改变的基因和途径的广泛景观，这将有助于设计靶向治疗的临床试验。
Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, and aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF3, FGF4, FGF19/CCND1 amplification, TP53 and CDKN2A alterations, appeared at more advanced stages in aggressive tumors. In 28% of the tumors we identified genetic alterations potentially targetable by 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.