title: Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer.
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.
authors.affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Valle
authors.forename: Tarsicio
authors.initials: T
authors.lastname: Serena-Acedo
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.forename: Ilene
authors.initials: I
authors.lastname: Comeras
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zeng
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pennison
authors.forename: Maureen
authors.initials: M
authors.lastname: Sadim
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Tanner
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human