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Published Online August 14, 2008
Science DOI: 10.1126/science.1159397

Reports

Submitted on April 21, 2008
Accepted on August 5, 2008

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 Chapelle 1*

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, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

* To whom correspondence should be addressed.
Boris Pasche , E-mail: b-pasche{at}northwestern.edu
Stephan M. Tanner , E-mail: Stephan.Tanner{at}osumc.edu
Albert de la Chapelle , E-mail: Albert.delaChapelle{at}osumc.edu

Much of the genetic predisposition to colorectal cancer (CRC) in humans is unexplained. Studying a Caucasian-dominated population in the United States, we show that germline allele-specific expression (ASE) of the gene encoding transforming growth factor–{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 transforming growth factor–{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 likely will show ethnic differences.

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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Infrequent Detection of Germline Allele-Specific Expression of TGFBR1 in Lymphoblasts and Tissues of Colon Cancer Patients.
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Science. ISSN 0036-8075 (print), 1095-9203 (online)