The Role of CDH1 -160 C/A Polymorphism in Gastric Cancer Metastasis: A Molecular Perspective

Authors

  • Ida Bagus Gede Ari Suryawan Faculty of Medicine, Udayana University Author
  • I G Mahapraja Divasta Faculty of Medicine, Udayana University Author
  • I Gede Aswin Parisya Sasmana Faculty of Medicine, Udayana University Author
  • I Gede Putu Supadmanaba Biochemistry Department, Faculty of Medicine, Udayana University Author

Keywords:

Diffuse gastric cancer, CDH1 -160 C/A polymorphism, E-cadherin deficiency, Epigenetic silencing cascade, Epithelial-Mesenchymal Transition (EMT)

Abstract

Primary gastric cancer is a formidable, biologically heterogeneous malignancy globally. Among its distinct histopathological subtypes, diffuse gastric cancer (DGC) is notoriously aggressive, characterized by extensive metastatic dissemination, profound therapeutic resistance, and devastating mortality. A foundational molecular defect driving this highly invasive phenotype is the loss of E-cadherin, a transmembrane glycoprotein encoded by the CDH1 tumor suppressor gene (chromosome 16q22.1). This systematic review elucidates the structural, molecular, and epigenetic implications of the CDH1 -160 C/A promoter polymorphism (rs16260), a critical genetic variant that significantly attenuates baseline transcription. This cytosine-to-adenine transversion alters the binding landscape for activating transcription factors (Sp1 and AP-2) while creating aberrant binding sites for transcriptional repressors. Furthermore, the variant -160A allele facilitates a lethal epigenetic silencing cascade mediated by non-coding sense promoter-associated RNAs (S-paRNAs), microRNA isomiR-4534, Argonaute 1 (AGO1), and histone methyltransferase SUV39H1, locking the CDH1 promoter in a hypermethylated state via DNMT recruitment. The resultant depletion of E-cadherin collapses epithelial adherens junctions, leading to the highly motile, signet ring morphology characteristic of linitis plastica. Concomitantly, the dissolution of E-cadherin scaffolding releases β-catenin into the cytoplasm, hyperactivating canonical Wnt/β-catenin signaling to drive proliferation, while non-canonical cytoskeletal dynamics driven by p120-catenin, Rac1, and mutant RhoA (Y42C) are rewired to promote motility. These synergistic cascades precipitate Epithelial-Mesenchymal Transition (EMT), driving lineage plasticity requisite for invasion. Finally, this report highlights translational precision oncology strategies targeting ROS1/FAK synthetic lethality, Wnt/β-catenin inhibition, and epigenetic reactivation via DNA demethylating agents.

Author Biographies

  • Ida Bagus Gede Ari Suryawan, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • I G Mahapraja Divasta, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • I Gede Aswin Parisya Sasmana, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • I Gede Putu Supadmanaba, Biochemistry Department, Faculty of Medicine, Udayana University

    Biochemistry Department, Faculty of Medicine, Udayana University

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2026-06-26

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Vol. 2 No. 1 (2026)

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