Methylation aberrations and genomic instability synergistically drive the evolution of intrahepatic cholangiocarcinoma

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. Intrahepatic cholangiocarcinoma (ICC) is a rare but aggressive type of liver cancer with a poor prognosis. In this study, we analyzed DNA methylation and genetic alterations in 341 ICC samples to understand how these molecular changes contribute to cancer progression. DNA methylation is a chemical modification to DNA that can switch genes on or off without changing the DNA sequence itself. Genomic instability, which refers to a high frequency of mutations across the genome, is a common feature of cancer. We found that abnormal DNA methylation occurs more frequently in advanced-stage ICC and can help distinguish advanced from early-stage disease, suggesting it could serve as a potential biomarker for cancer spread. We also observed greater genomic instability in advanced-stage ICC. Notably, the abnormal DNA methylation patterns were closely linked to genomic instability – especially in key cancer-related genes – potentially working together to disrupt normal gene function. Our findings provide new insights into how epigenetic and genetic alterations drive the development and progression of ICC and may support future efforts to develop new diagnostic tools or targeted treatments.