机构：[1]Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.[2]State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.[3]Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China.[4]Transvascular Implantation Devices Research Institute, Hangzhou, China.[5]Binjiang Institute of Zhejiang University, Hangzhou, China.[6]Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.浙江省肿瘤医院[7]Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.四川大学华西医院
DNA methylation and genomic instability are critical drivers of cancer initiation and malignant progression. However, the roles of methylation aberrations and genomic instability in malignant progression have not been thoroughly investigated in intrahepatic cholangiocarcinoma (ICC). To address this, we identified differentially methylated regions (DMRs) and somatic copy number alterations (SCNAs) from 341 ICC samples across various stages.Our findings revealed that stages IAIB, II, IIIA, and IIIB exhibited comparable methylation changes, whereas stage IV ICC showed a pronounced accumulation of stage-specific methylation alterations. Leveraging these findings, we developed a classification model that effectively distinguished stage IV ICC from earlier stages with high accuracy using 15 DMRs. Furthermore, stage IV ICC exhibited slightly higher genomic instability, including an elevated aneuploidy score and a greater proportion of focal amplifications. We also observed a positive correlation between SCNA burden and DNA methylation entropy in the promoter, gene body, and CpG island regions, with the gene body of MDM2 serving as a notable example.These findings highlight the potential of DNA methylation as a biomarker for metastasis diagnosis and the interplay between local genomic instability and aberrant methylation, emphasizing their synergistic roles in driving the evolutionary trajectory of ICC.
基金：
This manuscript was funded by the National Natural Science Foundation of China [Project 81773012] and the National Key Research and Development Program of China [2022YFA1105200 and 2023YFA1800700].The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|4 区医学
小类|4 区遗传学
最新[2025]版：
大类|4 区医学
小类|4 区遗传学
第一作者：
第一作者机构：[1]Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.[2]State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.[3]Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China.[4]Transvascular Implantation Devices Research Institute, Hangzhou, China.
通讯作者：
通讯机构：[1]Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.[2]State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.[3]Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China.[4]Transvascular Implantation Devices Research Institute, Hangzhou, China.[5]Binjiang Institute of Zhejiang University, Hangzhou, China.
推荐引用方式(GB/T 7714)：
Li Guanghao,Bai Youhuang,Tao Feng,et al.Methylation aberrations and genomic instability synergistically drive the evolution of intrahepatic cholangiocarcinoma[J].Epigenomics.2025,1-14.doi:10.1080/17501911.2025.2518919.
APA：
Li Guanghao,Bai Youhuang,Tao Feng,Hu Tingting,Wang Ting...&Sun Deqiang.(2025).Methylation aberrations and genomic instability synergistically drive the evolution of intrahepatic cholangiocarcinoma.Epigenomics,,
MLA：
Li Guanghao,et al."Methylation aberrations and genomic instability synergistically drive the evolution of intrahepatic cholangiocarcinoma".Epigenomics .(2025):1-14
