MUTATION OF THE TYPE-II TRANSFORMING-GROWTH-FACTOR-BETA RECEPTOR IS COINCIDENT WITH THE TRANSFORMATION OF HUMAN COLON ADENOMAS TO MALIGNANTCARCINOMAS

The transforming growth factor-p (TGF-P) type II receptor (RII) is a c olon cancer suppressor gene that is inactivated by mutation in 90% of human colon cancers arising via the microsatellite instability (MSI) p athway of carcinogenesis. To determine the pathophysiological conseque nce of RII mutations, we have determined the timing of their onset amo ng 22 MSI human colon adenomas of varying stages. No RII mutations mer e detected in any early MSI adenoma, including all those with simple t ubular or villous histology, The earliest RII mutation detected was in a region of high-grade dysplasia but was absent from the surrounding simple adenoma, Six additional RII mutations were all found in highly progressed adenomas that contained regions of frankly invasive adenoca rcinoma. These RII mutations were detected in both the advanced adenom as and their adjacent regions of carcinoma. RII mutation is a late eve nt in MSI adenomas and correlates tightly with progression of these ad enomas to cancer.