The frequent epigenetic silencing of RUNX3 in multiple solid tumor types indicates a strong RUNX3 gatekeeper role during early-stage cancer, while the abnormally elevated RUNX3 expression in pancreatic ductal adenocarcinoma indicates a role—in conjunction with TGFβ pathway component SMAD4/DPC4—in directing a metastatic transcriptional program [17,36]. The gene discussed is SMAD4; the disease is cancer.