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

Overview

Journal Science

Specialty Science

Date 2008 Aug 16

PMID 18703712

Citations 98

Authors

Laura Valle

Tarsicio Serena-Acedo

Sandya Liyanarachchi

Heather Hampel

Ilene Comeras

Zhongyuan Li

Qinghua Zeng

Hong-Tao Zhang

Michael J Pennison

Maureen Sadim

Boris Pasche

Stephan M Tanner

Albert de la Chapelle

Affiliations

Soon will be listed here.

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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