Genetic Landscape and Biomarkers of Hepatocellular Carcinoma
Genetic Landscape and Biomarkers of Hepatocellular Carcinoma
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DOI：
10.1053/j.gastro.2015.05.061
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发表时间：
2015-10-01
期刊：
影响因子：
29.4
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
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作者：
Zucman-Rossi, Jessica;Villanueva, Augusto;Llovet, Josep M.
肝细胞癌（HCC）已成为癌症相关死亡的主要原因。其死亡率在西方人口中有所增加，少数患者在早期诊断，当时治愈治疗是可行的。只有多激酶抑制剂索拉非尼可用于晚期病例的管理。在过去的10年中，已经清楚地描绘了HCC遗传改变的景观，包括染色体6p 21（VEGFA）和11 q13（FGF 19/CNND 1）的高水平DNA扩增，以及9号染色体（CDKN 2A）的纯合缺失。最常见的突变影响TERT启动子（60%），与端粒酶表达增加有关。拷贝数变异和B型肝炎病毒DNA插入也会影响TERT启动子的表达，并且在癌前病变中也会发生突变。TP 53和CTNNB 1是下一个最常见的突变，影响25%-30%的HCC患者，除了低频突变基因（例如，AXIN 1，ARID 2，ARID 1A，TSC 1/TSC 2，RPS 6 KA 3，KEAP 1，MLL 2）外，还有助于定义HCC中的一些核心失调途径。从概念上讲，其中一些变化表现为原型致癌成瘾环，是特定治疗方法的理想生物标志物。来自基因组分析的数据使得HCC在2个主要分子簇（增殖和非增殖）中的提议成为可能，在预后特征、途径激活和肿瘤表型中具有差异富集。将这些发现转化为具体的治疗决策是该领域未满足的医学需求。
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmeet medical need in this field.