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-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.The annual worldwide incidence of colorectal cancer (CRC) exceeds 1 million, being the second to fourth most common cancer in industrialized countries (1). Although diet and lifestyle are thought to have a strong impact on CRC risk, genes have a key role in the predisposition to this cancer. A positive family history of CRC occurs in 20 to 30% of all probands. Highly penetrant autosomal dominant and recessive hereditary forms of CRC account for at most 5% of all CRC cases (2). Although additional high-and low-penetrance alleles have been proposed, much of the remaining predisposition to CRC remains unexplained (3).Aberrations in the transforming growth factor-β (TGF-β) pathway are heavily involved in CRC carcinogenesis (4). Although mutations in the TGF-β type II receptor gene have been explicitly associated with CRC (5), the type I receptor gene (TGFBR1) has received less attention, although there is evidence that a common variant may be associated with cancer risk (6,7). We hypothesized that TGFBR1 is a notable candidate for a gene that, when mutated, causes predisposition to CRC or acts as a modifier of other genes, resulting in a predisposition. Our study was undertaken to test this assumption.

Targeting TGF-β Signaling for Therapeutic Gain

“…This could be remediated by optimized dosing strategies, but may require the development of new drugs against tissue-specific TGF-b signaling components that are active only on discrete cell types of the TME, such as GARP. Finally, if TGF-b blockade drugs are approved for widespread use, there will be considerable variation in both therapeutic and toxicological responses among patients (Bonyadi et al 1997;Akhurst 2004;Valle et al 2008;Benzinou et al 2012;Chung Kang et al 2013;Kawasaki et al 2014). There is therefore a growing need for development of predictive biomarkers of TGF-b blockade (Gueorguieva et al 2014;Kawasaki et al 2014).…”

Nonfluorescent Denaturing HPLC–Based Primer-Extension Method for Allele-Specific Expression: Application to Analysis of Mismatch Repair Genes

“…The other patient had a modest degree of imbalance, which, because the imbalance was borderline compared with the variation in allele expression observed in control individuals, is unlikely to play a major pathogenic role in this HNPCC patient. A pathogenic role cannot be excluded, however, because modest degrees of unbalanced allele expression demonstrated for other genes involved in colorectal carcinogenesis have been shown to have the potential to contribute to a cancer predisposition (11,26 ).…”

“…In addition, altered germline expression of alleles due to genetic (4 -7 ) and epigenetic (8,9 ) mechanisms has been shown to play a pathogenic role in monogenic diseases. Altered allele expression due to variation in gene copy number or to other mechanisms that affect the transcription and/or stability of individual genes has been hypothesized to be one of the main mechanisms involved in predisposition to polygenic disease (10,11 ). These considerations suggest that altered constitutive production of germline transcripts represents a powerful marker for analyzing genetic or epigenetic predisposition to cancer or other diseases.…”

Allele imbalance in the transcriptome of human hepatocellular carcinoma: stress-induced gene plays a role

“…Allele-specific expression analysis of APC has been proposed to be an important indicator of pathogenicity of familial adenomatous polyposis patients without APC mutations [11] . In addition to APC, allele-specific expression of TGFBR1 which results in reduced expression of the gene also confers an increased risk of colorectal cancer [12] . In addition to the increased cancer risk, the allele-specific imbalance also affects the prognosis and outcome of cancer patients.…”

“…Increasing evidences suggested that small changes in gene expression, which were regarded to be less-penetrant, might substantially contribution to cancer incidence and patient prognosis during cancer progression [3] . The alleles with functional defects were usually overrepresented in cancer cells, which resulted in the allele-specific imbalance in the cancer transcriptome, and confer risk to the patients [4] . In the April 2014 issue of Gastroenterology, we reported the allele-specific imbalance of Oxidative Stress Induced Growth Inhibitor 1 (OSGIN1) can significantly contribute to the progression of HCC.…”