Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Nat Commun. 2024 Nov 17;15(1):9960. doi: 10.1038/s41467-024-54387-8.
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, with poor prognosis and limited treatment options. The genomic features of ICC in Chinese patients remain largely unknown. In this study, we perform deep whole-exome sequencing of 204 Chinese primary ICCs and characterize genomic alterations and clonal evolution, and reveal their associations with patient outcomes. We identify six mutational signatures, including Signatures A and F, which are highly similar to previously described signatures linked to aristolochic acid and aflatoxin exposures, respectively. We also identify 13 significantly mutated genes in the ICC samples, including SAV1. We find that SAV1 was mutated in 2.9% (20/672) of 672 ICC samples. SAV1 mutation is associated with lower SAV1 protein levels, higher rates of tumor recurrence, and shorter overall patient survival. Biofunctional investigations reveal a tumor-suppressor role of SAV1: its inactivation suppresses Hippo signaling, leading to YAP activation, thereby promoting tumor growth and metastasis. Collectively, our results delineate the genomic landscape of Chinese ICCs and identify SAV1 as a potential driver of ICC.
肝内胆管癌 (ICC) 是继肝细胞癌之后第二大常见的原发性肝脏恶性肿瘤，预后较差，治疗选择有限。中国患者 ICC 的基因组特征在很大程度上尚不清楚。在这项研究中，我们对 204 例中国原发性 ICC 进行了深度全外显子组测序，对基因组改变和克隆进化进行了特征分析，并揭示了它们与患者预后的关系。我们确定了六个突变特征，包括特征 A 和特征 F，它们分别与先前描述的与马兜铃酸和黄曲霉毒素暴露相关的特征高度相似。我们还在 ICC 样本中鉴定出 13 个显著突变的基因，包括 SAV1。我们发现 SAV1 在 672 个 ICC 样本中的 2.9%（20/672）中发生了突变。SAV1 突变与较低的 SAV1 蛋白水平、更高的肿瘤复发率和更短的总体患者生存时间相关。生物功能研究揭示了 SAV1 的肿瘤抑制作用：其失活抑制 Hippo 信号通路，导致 YAP 激活，从而促进肿瘤生长和转移。总之，我们的研究结果描绘了中国 ICC 的基因组图谱，并确定 SAV1 是 ICC 的潜在驱动基因。
