||5R21CA082516-02 Interpret this number
||Northwestern University At Chicago
||Mutations of the Type 1 Tgf Beta Receptor in Cancer
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.
TGFBR1*6A may contribute to hereditary colorectal cancer.
, Caldes T.
, Wijnen J.
, Franken P.
, Vasen H.
, Kaklamani V.
, Nafa K.
, Peterlongo P.
, Ellis N.
, Baron J.A.
, et al.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2005-05-01; 23(13), p. 3074-8.
TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies.
, Hou N.
, Bian Y.
, Reich J.
, Offit K.
, Michel L.S.
, Rubinstein W.S.
, Rademaker A.
, Pasche B.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2003-09-01; 21(17), p. 3236-43.
TGF-beta signaling alterations in cancer.
, Kaklamani V.
, Reich J.
, Pasche B.
Cancer treatment and research, 2003; 115, p. 73-94.