Ueno Masayuki, Takeda Haruhiko, Takai Atsushi, Nakano Shigeharu, Fujii Yosuke, Mishima Masako, Iguchi Eriko, Inuzuka Tadashi, Shimizu Takahiro, Jinnouchi Keita, Haga Hironori, Hatano Etsuro, Seno Hiroshi
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki, Japan.
Liver Int. 2025 Jul;45(7):e70197. doi: 10.1111/liv.70197.
Multiple systemic therapies have received approval for hepatocellular carcinoma (HCC), necessitating the prediction of treatment efficacy to promote personalised treatment strategies. Mutational signatures reflect the mutational processes in human cancers and have emerged as promising biomarkers. In this study, we aimed to elucidate the acquisition process and clinical relevance of mismatch repair deficiency (dMMR)-associated mutational signatures.
First, we performed mutational signature analyses across various stages of hepatocarcinogenesis using multi-regional whole-genome sequencing data from 529 samples from 26 patients with or without HCC. Second, multi-omics analysis of an additional 239 HCC samples was conducted. Third, we analysed whole-exome sequencing data from 75 additional HCC samples to elucidate the effect of dMMR-associated signatures on the response to atezolizumab plus bevacizumab.
In the first analysis, dMMR-associated signatures were commonly observed in subclonal mutations in HCC, but were absent in noncancerous liver tissues. The second analysis revealed that a high proportion of dMMR-associated signatures were associated with larger tumour size, advanced tumour stages, upregulation of cell cycle-related genes, and lower expression of the IL6 gene, but not with decreased expression of mismatch repair genes. The third analysis showed that a high proportion of dMMR-associated signatures were significantly associated with better response rates and longer progression-free survival.
Our findings indicate that dMMR-associated signatures can accumulate in HCC without diminished expression levels of mismatch repair proteins, especially during the later stages of tumour progression. They can be a novel biomarker for predicting the efficacy of immunotherapy for HCC.
多种全身治疗方法已获批用于肝细胞癌（HCC）治疗，因此需要预测治疗效果以推动个性化治疗策略。突变特征反映了人类癌症中的突变过程，并已成为有前景的生物标志物。在本研究中，我们旨在阐明错配修复缺陷（dMMR）相关突变特征的获得过程及其临床相关性。
首先，我们使用来自26例有或无HCC患者的529个样本的多区域全基因组测序数据，对肝癌发生的各个阶段进行了突变特征分析。其次，对另外239个HCC样本进行了多组学分析。第三，我们分析了另外75个HCC样本的全外显子组测序数据，以阐明dMMR相关特征对阿替利珠单抗联合贝伐单抗治疗反应的影响。
在首次分析中，dMMR相关特征在HCC的亚克隆突变中普遍存在，但在非癌性肝组织中不存在。第二次分析显示，高比例的dMMR相关特征与更大的肿瘤大小、晚期肿瘤阶段、细胞周期相关基因的上调以及IL6基因的低表达相关，但与错配修复基因的表达降低无关。第三次分析表明，高比例的dMMR相关特征与更高的缓解率和更长的无进展生存期显著相关。
我们的研究结果表明，dMMR相关特征可在HCC中积累，而错配修复蛋白的表达水平不会降低，尤其是在肿瘤进展的后期。它们可能是预测HCC免疫治疗疗效的新型生物标志物。
