Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Hepatol Int. 2023 Dec;17(6):1461-1476. doi: 10.1007/s12072-023-10540-x. Epub 2023 May 23.
Relapse of hepatocellular carcinoma (HCC) due to vascular invasion is common, but the genomic mechanisms remain unclear, and molecular determinants of high-risk relapse cases are lacking. We aimed to reveal the evolutionary trajectory of microvascular invasion (MVI) and develop a predictive signature for relapse in HCC.
Whole-exome sequencing was performed on tumor and peritumor tissues, portal vein tumor thrombus (PVTT), and circulating tumor DNA (ctDNA) to compare the genomic profiles between 5 HCC patients with MVI and 5 patients without MVI. We conducted an integrated analysis of exome and transcriptome to develop and validate a prognostic signature in two public cohorts and one cohort from Zhongshan Hospital, Fudan University.
Shared genomic landscapes and identical clonal origins among tumor, PVTT, and ctDNA were observed in MVI ( +) HCC, suggesting that genomic changes favoring metastasis occur at the primary tumor stage and are inherited in metastatic lesions and ctDNA. There was no clonal relatedness between the primary tumor and ctDNA in MVI ( - ) HCC. HCC had dynamic mutation alterations during MVI and exhibited genetic heterogeneity between primary and metastatic tumors, which can be comprehensively reflected by ctDNA. A relapse-related gene signature named RGS was developed based on the significantly mutated genes associated with MVI and shown to be a robust classifier of HCC relapse.
We characterized the genomic alterations during HCC vascular invasion and revealed a previously undescribed evolution pattern of ctDNA in HCC. A novel multiomics-based signature was developed to identify high-risk relapse populations.
肝细胞癌（HCC）因血管侵犯而复发较为常见，但基因组机制尚不清楚，也缺乏高危复发病例的分子标志物。本研究旨在揭示微血管侵犯（MVI）的进化轨迹，并建立 HCC 复发的预测标志物。
对 5 例有 MVI 的 HCC 患者和 5 例无 MVI 的 HCC 患者的肿瘤及肿瘤旁组织、门静脉癌栓（PVTT）和循环肿瘤 DNA（ctDNA）进行全外显子测序，比较基因组图谱。我们对外显子组和转录组进行综合分析，在两个公共队列和复旦大学中山医院的一个队列中开发和验证了一个预后标志物。
在 MVI（+）HCC 中观察到肿瘤、PVTT 和 ctDNA 之间存在共享的基因组景观和相同的克隆起源，表明有利于转移的基因组变化发生在原发性肿瘤阶段，并在转移灶和 ctDNA 中遗传。在 MVI（-）HCC 中，原发性肿瘤和 ctDNA 之间没有克隆相关性。MVI 过程中 HCC 发生动态突变改变，原发性肿瘤和转移性肿瘤之间存在遗传异质性，ctDNA 可以全面反映这种异质性。根据与 MVI 相关的显著突变基因，我们建立了一个复发相关基因标志物 RGS，该标志物可作为 HCC 复发的可靠分类器。
我们描述了 HCC 血管侵犯过程中的基因组改变，并揭示了 HCC 中 ctDNA 以前未描述的进化模式。建立了一种新的基于多组学的标志物，用于识别高危复发人群。
