Table 2_Evolutionary dynamics of recurrent hepatocellular carcinoma under divergent immune selection pressures.xlsx

Hepatocellular carcinoma (HCC) is a highly lethal, aggressive malignancy. Little is known about the evolutionary trajectories of HCC and how clinical decision-making could be informed based on biopsies of the initial tumour. Here, we report the whole-exome sequencing of a unique series of resected HCC tumours and matched recurrences. This cohort included patients who received a liver transplant and who were immunosuppressed at time of recurrence, in comparison to patients who underwent liver resection for HCC and immunocompetent at time of recurrence, therefore facilitating analyses of immune selection in driving evolutionary divergence. We find extensive evolutionary divergence between baseline and recurrent tumours, with the majority of mutations in our cohort being private, in the process informing sampling guidelines for precision oncology in this disease. We also find no evidence that immunosuppression relaxes immune selection pressures, given the absence of a genomic footprint reflecting the presentation of neoantigens or altered dynamics of genomic evolution. We attribute this to the presence of genetic lesions that confer the capabilities of immune evasion in these tumours prior to transplantation, and then validate the link between immune selection pressures and the emergence of these lesions in publicly available HCC datasets. Our findings point to HCC as a cancer with extensive evolutionary divergence over time, partly defined by an irreversible, genetically determined trajectory towards immune escape.

肝细胞癌（Hepatocellular carcinoma, HCC）是一种致死率极高的侵袭性恶性肿瘤。目前学界对其演化轨迹，以及如何通过初始肿瘤活检结果指导临床决策的认知仍较为有限。本研究对一系列独特的手术切除肝细胞癌肿瘤及其配对复发灶开展了全外显子组测序（whole-exome sequencing）。本队列纳入两类患者：一类为接受肝移植且复发时处于免疫抑制状态的患者，另一类为因肝细胞癌接受肝切除且复发时免疫功能正常的患者，此举便于分析免疫选择在驱动肿瘤演化分化中的作用。研究发现基线肿瘤与复发肿瘤之间存在广泛的演化分化，本队列中绝大多数突变为私有突变，该发现可为该疾病的精准肿瘤学采样指南提供参考。鉴于未发现反映新抗原（neoantigens）呈递或基因组演化动态改变的基因组特征，本研究未观察到免疫抑制会减弱免疫选择压力的证据。我们将该现象归因于：移植前这些肿瘤中已存在赋予免疫逃逸能力的遗传病变；随后我们在公开的肝细胞癌数据集中验证了免疫选择压力与这类病变出现之间的关联。本研究结果表明，肝细胞癌是一种随时间推移发生广泛演化分化的癌症，其演化轨迹在一定程度上表现为不可逆转的、由遗传决定的免疫逃逸路径。