Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer |
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| Authors: | Valle Laura Serena-Acedo Tarsicio Liyanarachchi Sandya Hampel Heather Comeras Ilene Li Zhongyuan Zeng Qinghua Zhang Hong-Tao Pennison Michael J Sadim Maureen Pasche Boris Tanner Stephan M de la Chapelle Albert |
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| Institution: | Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. |
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| Abstract: | 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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