Whole-genome sequencing reveals the evolutionary trajectory of HBV-related hepatocellular carcinoma early recurrence.
Whole-genome sequencing reveals the evolutionary trajectory of HBV-related hepatocellular carcinoma early recurrence.
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DOI：
10.1038/s41392-021-00838-3
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发表时间：
2022-01-26
影响因子：
39.3
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Zhou SL;Zhou ZJ;Song CL;Xin HY;Hu ZQ;Luo CB;Luo YJ;Li J;Dai Z;Yang XR;Shi YH;Wang Z;Huang XW;Fan J;Zhou J
肝细胞癌患者因肿瘤早期复发率高，根治性切除后长期存活率较低。从原发性肝细胞癌到早期复发的肝细胞癌的基因组进化轨迹知之甚少。在这项研究中，我们对40对接受根治性切除的原发和早期复发的乙肝病毒(HBV)相关的肝癌进行了全基因组测序(WGS)，并对4例原发和复发的肿瘤进行了广泛采样。我们确定了两种复发模式：新发复发(18/40)，它在遗传上独立于原发肿瘤发展，携带不同的肝细胞癌驱动因素；以及祖先复发(22/40)，它与原发肿瘤克隆性相关，进展比新发复发更快。我们发现复发位置是复发模式的预测：远处复发倾向于显示从头开始的模式，而局部复发倾向于显示祖先模式。然后，我们揭示了在原发和复发肿瘤中观察到的基于亚克隆结构、驱动基因突变和突变过程的进化轨迹。多区域WGS在肝癌祖先复发中表现出时空异质性和多克隆性、单系性播散。此外，我们在bcl9中发现了复发特异性突变和拷贝数增加，导致Wnt/β-catenin信号激活和免疫排斥的肿瘤微环境，这表明bcl9可能成为治疗复发肝癌的新靶点。总而言之，我们的结果使我们能够以前所未有的清晰度观察与乙肝病毒相关的肝细胞癌早期复发过程中的基因组进化，为加深对肝细胞癌的了解提供重要的分子基础，并为个体化治疗改善患者存活率提供了重要的分子基础。
Patients with hepatocellular carcinoma (HCC) have poor long-term survival following curative resection because of the high rate of tumor early recurrence. Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC. In this study, we performed whole-genome sequencing (WGS) on 40 pairs of primary and early-recurrent hepatitis B virus (HBV)-related HCC tumors from patients who received curative resection, and from four patients whose primary and recurrent tumor were extensively sampled. We identified two recurrence patterns: de novo recurrence (18/40), which developed genetically independently of the primary tumor and carried different HCC drivers, and ancestral recurrence (22/40), which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence. We found that the recurrence location was predictive of the recurrence pattern: distant recurrence tended to display the de novo pattern, whereas local recurrence tended to display the ancestral pattern. We then uncovered the evolutionary trajectories based on the subclonal architecture, driver-gene mutations, and mutational processes observed in the primary and recurrent tumors. Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal, monophyletic dissemination in HCC ancestral recurrence. In addition, we identified recurrence-specific mutations and copy-number gains in BCL9, leading to WNT/β-catenin signaling activation and an immune-excluded tumor microenvironment, which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC. Collectively, our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence, providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
48
作者：
Roth, Andrew;Khattra, Jaswinder;Shah, Sohrab P.
通讯作者：
Shah, Sohrab P.
影响因子：
16.6
作者：
Bayard, Quentin;Meunier, Lea;Letouze, Eric
通讯作者：
Letouze, Eric
影响因子：
5.8
作者：
Saunders, Christopher T.;Wong, Wendy S. W.;Cheetham, R. Keira
通讯作者：
Cheetham, R. Keira