Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors
Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors
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DOI：
10.1016/j.jhep.2016.09.021
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发表时间：
2017-02-01
影响因子：
25.7
通讯作者：
Nakagawa, Hidewaki
中科院分区：
文献类型：
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作者：
Furuta, Mayuko;Ueno, Masaki;Nakagawa, Hidewaki
背景和目标：肝细胞癌（HCC）患者由于肝脏中的强致癌背景而具有多中心（MC）肿瘤发生的高风险。此外，它们具有肝内转移（IM）的高风险。肝肿瘤伴IM或MC在其发展和临床结局方面有很大不同。然而，在临床或病理上区分IM和MC可能具有挑战性。本研究探讨了IM或MC是否可以在分子水平上诊断。方法：我们对23名HCC患者的49个肿瘤进行了全基因组和RNA测序分析，其中包括2个肝外转移瘤和1个结节中结节肿瘤。结果：排序-与先前的技术相比，使用体细胞单核苷酸变异信息的基于分子的诊断显示出更高的灵敏度，这是由于包含了大量的突变事件这在临床诊断不一致的病例中证明是有用的。此外，全基因组测序在分析其他遗传变异（如结构变异、拷贝数变异和变异等位基因频率）方面具有优势，并有助于确认IM/MC诊断。索拉非尼治疗的IM肿瘤之间的差异性变化、长时间间隔或肿瘤中肿瘤结节表明肝癌的高肿瘤内异质性、演变和克隆转换。结论：在选择肝脏多肿瘤的治疗策略之前，除了IM/MC诊断外，分析IM肿瘤之间的差异非常重要。多个肝脏肿瘤的全基因组测序使得能够利用体细胞单核苷酸变异信息准确诊断多中心发生和肝内转移。此外，肿瘤之间的遗传差异有助于我们了解复发和癌症扩散期间的物理变化。(C)2016年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors with IM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level.Methods: We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients.Results: Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MC diagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers.Conclusions: It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver.Lay summary: Whole genome sequencing of multiple liver tumors enabled the accurate diagnosis of multi-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.