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Mutations of the type 1 TGF beta receptor in cancer

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Transforming Growth Factor Beta (TGF-beta) is one of the most potent naturally occurring inhibitors of normal cell growth. TGF-beta exerts its action by binding to a type I (TbR-I) and a type II (TbR-II) transmembrane receptor located on the cell membrane. Downstream signaling is mediated by TbR-I once the ligand has bound both receptors. Three proteins, Smad2, Smad3 and Smad4/DPC4 have been found to be essential downstream components of the TGF-beta signaling pathway in mammalian cells. My work has led to the discovery of the first mutations of the type I TGF-beta receptor, a 9-bp deletion and 3-bp insertion coined TbR-I(6A) and TbR-I(10A), respectively. My most recent data indicate that the frequency of TbR-I(6A) heterozygotes and homozygotes is significantly higher in patients with cancer than in healthy blood donors of comparable ethnic status. However, TbR-I(6A) heterozygotes and especially TbR-I(6A) homozygotes carriers appear to be at greater risk of developing cancer. This observation is particularly striking in colorectal cancer. Indeed, 19 percent of the patients studied so far exhibited TbR-I(6A) homozygosity or heterozigosity. Stable transfection of mink lung epitheliall cell lines devoid of TbR-I with either TbR-I or TbR-I(6A) shows that TbR-l(6A) transduces less effectively TGF-beta mediated growth inhibition than TbR-I. Thus, TbR-I(6A) acts as a common TbR-I polymorphic allele compatible with normal human development. The higher than expected number of TbR-I(6A) heterozygotes and especially TbR-I(6A) homozygotes among cancer patients suggests that TbR-I(6A) is a candidate tumor susceptibility allele. This application's objectives are to test further the hypothesis that TbR-I(6A) and/or TbRI(10A) may be associated with the development of malignancy. It aims at determining: 1) The prevalence of TbR-I(6A) heterozygosity and homozygosity among the various ethnic groups of a healthy population, 2) Which human cancers may or may not be associated with the homozygous TbR-I(6A) and heterozygous TbR-I(6A) genotype, 3) Whether TbR-I(6A) is associated with certain forms of hereditary colon cancer, 4) The turnover as well as the proportion of cell surface and intracellular TbR-I and TbR-I(6A) receptors. Should TbR-I(6A) turn out to be a tumor susceptibility allele, the plan described in this application will serve as a basis for planning future clinical project grant applications. TbR-I(6A) homozygotes and TbR-I(6A) heterozygous carriers may have a higher risk to develop certain forms of cancer and may benefit from early screening. The clinical course of TbR-I(6A) carriers will need to be investigated as TbR-I status may have prognostic significance. Hence, this project has a high potential for translation of research to clinical applications.

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