Methylation Fingerprints of Colorectal Cancer: From Normal Tissue to Liver and Brain Metastasis

Ayvaz Ş., Turan B., Batan N., İnan C.

Annual Congress of the European Association for Cancer Research (EACR 2026), Budapest, Macaristan, 8 - 11 Haziran 2026, ss.1, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: Budapest
  • Basıldığı Ülke: Macaristan
  • Sayfa Sayıları: ss.1
  • Karadeniz Teknik Üniversitesi Adresli: Evet

Özet

Introduction

Colorectal cancer (CRC) progression from normal mucosa to metastasis involves extensive epigenetic reprogramming. Beyond genetic alterations, DNA methylation is critical for tumor initiation and the acquisition of organotropic metastatic phenotypes. This study systematically defines conserved and divergent methylation signatures across the adenoma-carcinoma-metastasis sequence to identify core gene sets and biomarkers for organ-specific progression.

Material and method

DNA methylation data (GSE28094) were retrieved from GEO. Samples included normal colon (n=97), adenoma (n=12), primary tumor (n=110), liver metastasis (n=32), and brain metastasis (n=13). Pairwise differential methylation was assessed using the limma package (FDR<0.05). Core targets shared across all disease groups were analyzed via GO-BP/KEGG enrichment, STRING-based protein-protein interaction (PPI) networks and hub gene identification. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis.

Results and discussion

Significant differentially methylated genes (DMGs) relative to normal tissue were 935 for adenoma, 743 for primary tumor, 772 for liver metastasis, and 991 for brain metastasis. Adenoma was predominantly hypomethylated (819/935), whereas hypermethylation was more frequent in primary tumors and liver metastases. Brain metastases showed significant divergence from both primary and liver lesions (707 and 720 targets, respectively), supporting organotropic epigenetic differentiation. We identified a core set of 114 Hyper and 138 Hypo targets shared across all stages. Enrichment analysis linked the Hyper set to epithelial proliferation and MAPK signaling, while the Hypo set was associated with gland morphogenesis, ECM remodeling, and hypoxia. PPI networks revealed Hyper hubs centered on angiogenesis axes (FGF8/FGFR1, KDR/FLT4) and Hypo hubs driven by EGFR, CTNNB1, and IL6. ROC analysis identified FGF8 as a superior Hyper hub (AUC=0.958) with CTNNB1 (AUC=0.836) and HGF (AUC=0.803) as leading Hypo hubs.

Conclusion

Our findings demonstrate a conserved core epigenetic signature across CRC stages. The distinct methylation profiles in brain metastasis suggest that metastatic adaptation is epigenetically regulated. These hub genes and high-AUC regions represent robust biomarker candidates for early diagnosis and stage-specific targeted therapies.

Acknowledgements

We acknowledge the authors who generated and deposited GSE28094 (Fernandez et al.) and GEO/NCBI for providing access to the publicly available data used in this study.