The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Commun. 2024 Aug 6;15(1):6690. doi: 10.1038/s41467-024-50850-8.
Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.
循环无细胞 DNA（cfDNA）正成为癌症检测的一个途径，但血液中 cfDNA 片段的特征尚不清楚。我们通过对 969 个人的分析，评估了 DNA 甲基化和基因表达对全基因组 cfDNA 片段化的影响。cfDNA 片段末端更频繁地包含 CCs 或 CGs，并且分别在甲基化 CpG 位置富集或耗尽以 CGs 或 CCGs 结尾的片段。cfDNA 片段的更高水平和更大尺寸与 CpG 甲基化和基因表达减少相关。这些效应在具有或不具有突变 IDH1 的同基因肿瘤的小鼠中得到了验证，并且与癌症患者 cfDNA 片段化的全基因组变化相关。肿瘤相关的低甲基化和基因表达增加与 cfDNA 片段大小的减少相关，这可能解释了人类癌症中较小的 cfDNA 片段。这些结果提供了表观遗传变化与 cfDNA 片段化之间的联系，对疾病检测具有重要意义。
