Cancer-associated fibroblasts reveal aberrant DNA methylation across different types of cancer

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. Several studies demonstrated molecular differences between CAFs and normal tissue-associated fibroblasts (NAFs). In this study, we isolated CAFs and NAFs from liver tumors and analyzed their DNA methylation profiles. A subset of the CAFs exhibited aberrant DNA methylation, which was also reflected on gene expression level. The DNA methylation at liver-CAF-specific CG dinucleotides (CpGs) was associated with survival in liver cancer data. An integrative analysis with public datasets of CAF versus NAF in different cancer types, including lung, prostate, esophagus, and gastric cancer, revealed overlapping epigenetic aberrations. CpGs with common aberrations in DNA methylation included cg09809672 (EDARADD), cg07134930 (HDAC4), and cg05935904 (intergenic). Aberrant DNA methylation at these sites was associated with prognosis in several cancer types. Thus, activation of CAFs by the tumor environment is associated with characteristic epigenetic modifications that could be used as biomarkers for disease stratification.