Identification of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratification by integrative multi-omics analysis
Identification of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratification by integrative multi-omics analysis
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通过综合多组学分析鉴定乙型肝炎病毒相关肝细胞癌的预后生物标志物和分层
DOI：
10.1016/j.jhep.2014.05.025
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发表时间：
2014-10-01
影响因子：
25.7
通讯作者：
Zhao, Haitao
中科院分区：
文献类型：
--
作者：
Miao, Ruoyu;Luo, Haitao;Zhao, Haitao
背景 82 目的：不同的多灶性肝细胞癌 (HCC) 的区分：多中心疾病与肝内转移，其中治疗和预后存在很大差异，仍然存在问题。作为多组学策略的一部分，我们的目标是通过进行全基因组和转录组测序来对多灶性 HCC 进行分层，并确定新的诊断和预后生物标志物。方法：从表现出两种不同术后病程的多灶性 HCC 代表性患者中获取完整的肿瘤和体细胞标本（肝内 HCC 病变、匹配的非癌性肝组织和血液）。对每个组织样本进行全基因组和转录组测序以及基因分型，以对比基因组改变，包括乙型肝炎病毒整合、体细胞突变、拷贝数变异和结构变异。然后，我们构建了系统发育树来可视化个体肿瘤进化，并对选定的差异表达基因进行功能富集分析，以阐明多灶性 HCC 发展中涉及的生物过程。将多组学数据与详细的临床病理学信息相结合，以确定 HCC 生物标志物，并使用大量 HCC 患者 (n = 174) 进一步验证。结果：多组学分析和肿瘤生物标志物可以成功区分两种多灶性 HCC 类型，同时准确预测克隆性和侵袭性。双特异性蛋白激酶 TTK 是一种与 p53 信号传导相关的关键有丝分裂检查点调节因子，在大型患者队列中被进一步证明是一种有前途的 HCC 总体预后标志物。结论：多灶性肿瘤进化的全面多组学特征可以改善临床决策，促进个性化医疗，并加快新型生物标志物和治疗方法的鉴定。 HCC 的目标。 (C) 2014 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background 82 Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy.Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.