PCDHGB6 (protocadherin gamma subfamily B, 6) is a potential calcium-dependent cell-adhesion protein that may be involved in establishing and maintaining specific neuronal connections in the brain. However, its primary clinical significance lies in its role as a tumor suppressor gene marker through promoter hypermethylation across multiple cancer types. PCDHGB6 promoter methylation occurs frequently in lung cancer (41.4% of patients vs 1.3% of healthy controls) 1 and breast cancer (methylated in more than 10 of 21 primary breast cancers) 2. This hypermethylation likely silences PCDHGB6 expression, contributing to tumorigenesis. The methylation pattern serves as a valuable biomarker for cancer detection, with combined analysis of PCDHGB6 and other genes achieving up to 90% sensitivity for cancer detection 3. Notably, PCDHGB6 methylation can be detected non-invasively in oral epithelium for lung cancer risk stratification, particularly in smokers 4, and in bronchial brushing specimens with 80% sensitivity 5. Additionally, germline variants in PCDHGB6 may contribute to susceptibility for certain lymphomas 6 and methamphetamine dependence 7, though these associations require validation.