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    Impact of 5HydroxyMethylCytosine (5hmC) on reverse/direct association of cell-cycle, apoptosis, and extracellular matrix pathways in gastrointestinal cancers
    (Springer, 2022) Moravveji, Sayyed Sajjad; Khoshbakht, Samane; Mokhtari, Majid; Salimi, Mahdieh; Lanjanian, Hossein; Nematzadeh, Sajjad; Torkamanian-Afshar, Mahsa; Masoudi-Nejad, Ali
    Background: Aberrant levels of 5-hydroxymethylcytosine (5-hmC) can lead to cancer progression. Identifcation of 5-hmC-related biological pathways in cancer studies can produce better understanding of gastrointestinal (GI) cancers. We conducted a network-based analysis on 5-hmC levels extracted from circulating free DNAs (cfDNA) in GI cancers including colon, gastric, and pancreatic cancers, and from healthy donors. The co-5-hmC network was reconstructed using the weighted-gene co-expression network method. The cancer-related modules/subnetworks were detected. Preservation of three detected 5-hmC-related modules was assessed in an external dataset. The 5-hmC-related modules were functionally enriched, and biological pathways were identifed. The relationship between modules was assessed using the Pearson correlation coefcient (p-value<0.05). An elastic network classifer was used to assess the potential of the 5-hmC modules in distinguishing cancer patients from healthy individuals. To assess the efciency of the model, the Area Under the Curve (AUC) was computed using fve-fold cross-validation in an external dataset. Results: The main biological pathways were the cell cycle, apoptosis, and extracellular matrix (ECM) organization. Direct association between the cell cycle and apoptosis, inverse association between apoptosis and ECM organiza? tion, and inverse association between the cell cycle and ECM organization were detected for the 5-hmC modules in GI cancers. An AUC of 92% (0.73–1.00) was observed for the predictive model including 11 genes. Conclusion: The intricate association between biological pathways of identifed modules may reveal the hidden signifcance of 5-hmC in GI cancers. The identifed predictive model and new biomarkers may be benefcial in cancer detection and precision medicine using liquid biopsy in the early stages.