We have recently demonstrated that a Smad4 mutation, Smad4 C324Y, isolated from nodal metastases of papillary thyroid carcinoma (33), determines a significant increase of TGF-β signaling, causing the acquisition of transformed phenotype and invasive behaviour when stably expressed in thyroid cells (22). The gene discussed is TGFB1; the disease is thyroid gland papillary carcinoma.