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Science 321 (5894): 1361-1365

Copyright © 2008 by the American Association for the Advancement of Science

Germline Allele-Specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer

Laura Valle,1 Tarsicio Serena-Acedo,1 Sandya Liyanarachchi,1 Heather Hampel,1 Ilene Comeras,1 Zhongyuan Li,1 Qinghua Zeng,2 Hong-Tao Zhang,2 Michael J. Pennison,2 Maureen Sadim,2 Boris Pasche,2* Stephan M. Tanner,1* Albert de la Chapelle1*

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–β (TGF-β) 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-β 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.

1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
2 Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

* To whom correspondence should be addressed. E-mail: b-pasche{at} (B.P.); Stephan.Tanner{at} (S.M.T.); Albert.delaChapelle{at} (A.d.l.C.)

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