Progression from minimally dysplastic epithelium to dysplasia to invasive carcinoma reflects the stepwise accumulation of gene mutations that either activate oncogenes (e.g. KRAS2), or inactivate tumor suppressor genes (e.g. CDKN2a/INK4a, TP53 and DPC4/SMAD4)5. The gene discussed is SMAD4; the disease is invasive carcinoma.