Journal
SCIENCE
Volume 321, Issue 5894, Pages 1361-1365Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1159397
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Funding
- NIH [CA67941, CA16058, CA112520, CA108741]
- Walter S. Mander Foundation
- Jeannik M. Littlefield-American Association for Cancer Research Grant in Metastatic Colon Cancer Research
- Fundacion Ramon Areces.
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Much of the genetic predisposition to colorectal cancer (CRC) in humans is unexplained. Studying a Caucasian- dominated population in the United States, we showed that germline allele- specific expression ( ASE) of the gene encoding transforming growth factor-beta (TGF-beta) type I receptor, TGFBR1, is a quantitative trait that occurs in 10 to 20% of CRC patients and 1 to 3% of controls. ASE results in reduced expression of the gene, is dominantly inherited, segregates in families, and occurs in sporadic CRC cases. Although subtle, the reduction in constitutive TGFBR1 expression alters SMAD- mediated TGF-beta signaling. Two major TGFBR1 haplotypes are predominant among ASE cases, which suggests ancestral mutations, but causative germline changes have not been identified. Conservative estimates suggest that ASE confers a substantially increased risk of CRC ( odds ratio, 8.7; 95% confidence interval, 2.6 to 29.1), but these estimates require confirmation and will probably show ethnic differences.
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