PCDHGC3 is a calcium-dependent cell adhesion molecule belonging to the protocadherin family, which are type I transmembrane proteins primarily expressed in the central nervous system 1. The protein localizes to cell-cell contact sites and mediates calcium-dependent cell adhesion 1. PCDHGC3 undergoes regulated ectodomain shedding via ADAM10-dependent proteolysis, a process that modulates its adhesive function 2. Despite initial classification as a potential tumor suppressor based on its adhesion properties, PCDHGC3 displays complex and context-dependent roles in cancer. In colorectal cancer, PCDHGC3 hypermethylation occurs during the adenoma-carcinoma transition, correlating with reduced expression and enhanced Wnt/mTOR signaling 3. Similarly, in neuroendocrine tumors and pheochromocytomas/paragangliomas, PCDHGC3 hypermethylation associates with increased metastatic potential and poor prognosis 45. Notably, in SDHB-mutated paragangliomas, PCDHGC3 promoter methylation can predict metastasis years before clinical manifestation 4. Conversely, in glioblastoma, PCDHGC3 shows elevated expression correlated with longer progression-free survival, suggesting tumor-suppressive functions 6. In clear cell renal carcinoma, altered PCDHGC3 expression via miRNA dysregulation correlates with prognosis 7. These divergent roles indicate PCDHGC3 functions as an epigenetically regulated biomarker with cancer-type-specific clinical significance.