肝细胞癌（HCC）是一种高度致命的癌症，其特点是肿瘤内异质性高（ITH）。全面了解其肿瘤演变及其临床轨迹，可能会提供新的预后和治疗策略。通过亚太肝细胞癌 (AHCC) 试验组 (NCT03267641)，我们招募了最大的 HCC 前瞻性队列之一来自 123 名初治患者的 600 多个全基因组和转录组样本。使用多区域采样方法，我们揭示了由早期驱动突变、晚期拷贝数变异和病毒整合控制的 7 条趋同遗传进化路径，这些路径对治疗后患者的临床轨迹进行了分层手术切除。此外，这种进化路径塑造了分子谱，导致不同的转录组亚型。最重要的是，尽管我们发现某些肿瘤内存在多种转录组亚型，但最好通过肿瘤中最具侵袭性的细胞部分来预测患者预后，而不是通过转录组 ITH 水平的总体程度来预测 - 这种现象我们称之为“坏苹果”影响。最后，我们发现早期和晚期肿瘤进化的特征为预测患者生存提供了重要且互补的预后能力。总之，我们的研究生成了 HCC 进化史的全面图景，并为理解肿瘤异质性和临床轨迹。NCT03267641（观察队列）影响和意义：这项前瞻性研究利用来自手术切除的 HCC 的综合多部门、多组学测序和临床数据，揭示了对肿瘤进化和肿瘤内异质性 (ITH) 的作用的重要见解）确定肝细胞癌（HCC）的预后。这些发现对于肿瘤学研究人员和临床医生来说非常宝贵，因为它们强调了不同进化路径和“坏苹果”效应的影响，其中最具侵袭性的肿瘤部分决定了疾病进展。这些见解不仅提高了手术切除后的预后准确性，而且还为开发针对特定肿瘤进化和转录组谱的个性化疗法铺平了道路。同一肿瘤内多种亚型的共存促使人们重新评估依赖单个样本代表整个肿瘤的效用，并表明需要临床分子成像。因此，这项研究标志着 HCC 的临床理解和管理向前迈出了重要一步，强调了将肿瘤进化动力学和多组学生物标志物整合到治疗决策中的重要性。版权所有 © 2024。由 Elsevier B.V. 出版。

Hepatocellular Carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies.Through the Asia-Pacific Hepatocellular Carcinoma (AHCC) trials group (NCT03267641), we recruited one of the largest prospective cohorts of HCC with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients.Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival.Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provided a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories.NCT03267641 (Observational cohort) IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected HCC, reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of Hepatocellular Carcinoma (HCC). These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for developing personalized therapies tailored to specific tumor evolutionary and transcriptomic profiles. The co-existence of multiple sub-types within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making.Copyright © 2024. Published by Elsevier B.V.