RASSF2 is a tumor suppressor gene that acts as a KRAS-specific effector protein 1. It functions through multiple mechanisms: stabilizing the Hippo kinase MST2/STK3 by protecting it from proteasomal degradation 1, promoting apoptosis and cell cycle arrest 1, and regulating Rac GTPase signaling through interaction with the guanine nucleotide exchange factor DOCK2 2. In t(8;21) acute myeloid leukemia, RASSF2 is transcriptionally repressed by the RUNX1-ETO fusion protein; its re-expression inhibits leukemia development via Hippo kinase-dependent mechanisms independent of canonical Hippo pathway signaling 2. RASSF2 inactivation occurs primarily through CpG island promoter hypermethylation across multiple cancer types. In colorectal cancer, RASSF2 methylation frequently co-occurs with KRAS/BRAF mutations and enhances Ras-induced transformation 3. Similar hypermethylation-mediated silencing occurs in gastric cancer 4, gastric cardia adenocarcinoma 5, esophageal squamous cell carcinoma 6, diffuse gliomas 7, and breast cancer—where hypermethylation is associated with better prognosis in luminal subtypes 8. RASSF2 methylation status serves as a biomarker for malignant progression and patient survival prediction across multiple malignancies.