INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 75013 Paris, France.
Cancer Cell. 2014 Apr 14;25(4):428-41. doi: 10.1016/j.ccr.2014.03.005.
Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.
肝细胞腺瘤（HCA）是一种良性肝肿瘤，主要发生在使用口服避孕药的女性中。在这里，外显子组测序发现了复发性体细胞 FRK 突变，这些突变诱导组成性激酶活性、STAT3 激活和对Src 抑制剂敏感的细胞增殖。我们还发现了常见的复发性突变，这些突变激活了 JAK1、gp130 或β-catenin。染色体拷贝数和甲基化谱分析显示出与特定基因突变和肿瘤表型相关的模式。最后，对转化为肝细胞癌的 HCA 的综合分析显示，β-catenin 突变是早期改变，而 TERT 启动子突变与腺瘤-癌转化序列的最后一步相关。总之，我们确定了良性肝细胞增殖的基因组多样性、几个治疗靶点以及腺瘤-癌转化序列的关键基因组决定因素。
