Clonal evolution in long-term follow-up patients with hepatocellular carcinoma
Clonal evolution in long-term follow-up patients with hepatocellular carcinoma
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DOI：
10.1002/ijc.31844
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发表时间：
2018-12-01
影响因子：
6.4
通讯作者：
Liu, Jingfeng
中科院分区：
文献类型：
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作者：
Chen, Geng;Cai, Zhixiong;Liu, Jingfeng
为了研究肝细胞癌(HCC)的肿瘤克隆演化，我们收集了31例肿瘤标本、16例瘤周标本和11例长期随访患者的配对PBMC。对每个样本进行全外显子组测序，获得SNV和CNV。平均每例患者发现652.2个体细胞突变，其中非普遍存在的肿瘤突变的平均百分比为63.7%(范围为0.7%-100%)，反映了肿瘤异质性的多样性。基于突变聚类结果对克隆进化的进一步分析表明，单灶性和多灶性肝癌确实存在不同的克隆进化模式，且这些模式与患者的临床病程显着相关。这些模式清楚地表明了肿瘤复发的不同机制。在肿瘤克隆进化过程中，潜在的治疗靶点也会动态地出现和消失。此外，突变分析表明突变特征的贡献与克隆进化史有关。对后续血浆样本进行靶点测序也证实了ctDNA水平可以动态反映肿瘤克隆/亚克隆负荷。通过研究肝癌患者的克隆进化，我们的分析揭示了在肝癌进展过程中确实存在不同的模式，并提出了一种新的策略来识别复发肿瘤的来源以及优化治疗选择。
To investigate tumor clonal evolution in hepatocellular carcinoma (HCC), we collected 31 tumor samples,16 peritumor samples and matched PBMCs from 11 long-term follow-up patients with HCC. Whole-exome sequencing was performed to obtain SNVs and CNVs for each sample. An average of 652.2 somatic mutations were identified in each patient and the mean percentage of nonubiquitous tumor mutations was 63.7% (range, 0.7%-100%), reflecting the variety of tumor heterogeneity. Further analysis of clonal evolution was conducted based on mutation clustering results and revealed that different clonal evolution patterns indeed existed in single and multifocal HCC while these patterns were significantly correlated to patients' clinical course. These patterns clearly demonstrated different mechanisms of tumor recurrence. During tumor clonal evolution, potential therapeutic targets also emerged and vanished dynamically. Moreover, mutation analysis revealed that the contribution of mutational signature was correlated with clonal evolution history. Target sequencing of follow-up plasma samples also confirmed that ctDNA level could dynamically reflect tumor clonal/subclonal burden. By investigating clonal evolution in HCC patients, our analysis revealed that different patterns indeed existed during HCC progression and proposed a novel strategy for identifying the origin of recurrent tumor as well as optimizing treatment selection.