Germline Allele-Specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer
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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.
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Preclinical studies highlight extensive influences of germline genetic modifiers of TGF-β activity on tumorigenesis, vascular integrity, and allergy.
“preclinical studies highlight extensive influences of germline genetic modifiers of TGF-β activity on tumorigenesis, vascular integrity and allergy392,398–400.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [392]
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- Authors
- Valle, L., Serena-Acedo, T., Liyanarachchi, S., Hampel, H., Comeras, I., Li, Z., Zeng, Q., Zhang, H.-T., Pennison, M. J., Sadim, M., Pasche, B., Tanner, S. M., & de la Chapelle, A.
- Affiliations
- Northwestern University (US)
- Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
- Corresponding author
- Pasche, Boris
- Tanner, Stephan M.
- Venue
- Science
- Published
- 2008-09-05
- Volume
- 321
- Issue
- 5894
- Pages
- 1361-1365
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2672914
- OpenAlex
- W2164398315
- Cited by
- 141
- References
- 30
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 8 · 2015: 2 · 2014: 10 · 2013: 12 · 2012: 10
- FWCI
- 13.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca112520-08)
- National Cancer Institute (CA112520, CA108741, R01CA108741, CA67941, CA16058, R01-CA112520, P30CA012197, P30CA016058)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- colorectal cancer, allele-specific expression, TGFBR1, germline mutations, genetic susceptibility, Smad signaling, TGF-beta signaling, haplotypes, cancer risk, family segregation, Caucasian population
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Adult, Aged, Aged, 80 and over, Alleles, Cell Line, Female, Haplotypes, Heterozygote, Humans, Male, Middle Aged, Risk Factors, Colorectal Neoplasms, Signal Transduction, Linkage Disequilibrium, Gene Expression, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Quantitative Trait, Heritable, Genetic Predisposition to Disease, 3' Untranslated Regions, Polymorphism, Single Nucleotide, Smad3 Protein
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