Loss of expression of SMAD4 (SMAD family member 4), which is a critical component of the transforming growth factor β signaling pathway together with SMAD2 and 3, and is located on 18q, a frequent site of loss of heterozygosity (LOH), is linked to the transition from adenoma to high-grade carcinoma and is associated with the JP syndrome. The gene discussed is SMAD4; the disease is adenoma.