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Grant Details

Grant Number: 5R21CA082516-02 Interpret this number
Primary Investigator: Pasche, Boris
Organization: Northwestern University At Chicago
Project Title: Mutations of the Type 1 Tgf Beta Receptor in Cancer
Fiscal Year: 2002
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Abstract

DESCRIPTION (provided by applicant): 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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Publications

TGFBR1*6A may contribute to hereditary colorectal cancer.
Authors: Bian Y. , Caldes T. , Wijnen J. , Franken P. , Vasen H. , Kaklamani V. , Nafa K. , Peterlongo P. , Ellis N. , Baron J.A. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2005-05-01; 23(13), p. 3074-8.
PMID: 15860866
Related Citations

TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies.
Authors: Kaklamani V.G. , Hou N. , Bian Y. , Reich J. , Offit K. , Michel L.S. , Rubinstein W.S. , Rademaker A. , Pasche B. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2003-09-01; 21(17), p. 3236-43.
PMID: 12947057
Related Citations

TGF-beta signaling alterations in cancer.
Authors: Bian Y. , Kaklamani V. , Reich J. , Pasche B. .
Source: Cancer treatment and research, 2003; 115, p. 73-94.
PMID: 12613193
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