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

<h4>Aims & methods</h4>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.<h4>Results</h4>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 <i>MDM2</i> serving as a notable example.<h4>Conclusions</h4>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.