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TbetaR-I(6A) is a candidate tumor susceptibility allele
B Pasche1, P Kolachana, K Nafa
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Research
|December 3, 1999
Summary
The type I transforming growth factor-beta receptor (TbetaR-I) 6A allele is linked to increased cancer risk. This TbetaR-I(6A) variant impairs TGF-beta signaling, potentially contributing to tumor development, especially in colon cancer.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- A specific polymorphic allele of type I transforming growth factor-beta receptor (TbetaR-I), known as TbetaR-I(6A), has been identified.
- This allele is characterized by a deletion of three alanines within a nine-alanine stretch in the receptor.
- An elevated frequency of TbetaR-I(6A) homozygotes was previously observed in cancer patients' DNA.
Purpose of the Study:
- To investigate the association between TbetaR-I(6A) homozygosity and cancer.
- To determine the germ-line frequencies of the TbetaR-I(6A) allele in cancer patients and healthy controls.
- To elucidate the functional impact of the TbetaR-I(6A) allele on TGF-beta signaling.
Main Methods:
- A case-control study was conducted comparing cancer patients with matched healthy individuals.
- Germ-line DNA was analyzed to determine the frequencies of TbetaR-I(6A) homozygotes and heterozygotes.
- Functional assays using stably transfected cell lines (TbetaR-I and TbetaR-I(6A)) were performed to assess TGF-beta signaling capacity.
Main Results:
- Nine TbetaR-I(6A) homozygotes were identified among 851 cancer patients, versus none in 735 healthy controls (P < 0.01).
- A significantly higher proportion of heterozygotes for TbetaR-I(6A) was found in cancer cases (14.6%) compared to controls (10.6%) (P = 0.02).
- Subset analysis showed 4 of 112 colorectal cancer patients were TbetaR-I(6A) homozygotes (P < 0.01).
- Functional studies revealed that TbetaR-I(6A) is impaired in mediating TGF-beta antiproliferative signals compared to wild-type TbetaR-I.
Conclusions:
- The TbetaR-I(6A) allele is associated with an increased susceptibility to cancer.
- This tumor susceptibility may arise from diminished TGF-beta-mediated growth inhibition.
- The TbetaR-I(6A) allele is particularly implicated in the development of colon cancer.
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