Comprehensive assessment of variation at the transforming growth factor β type 1 receptor locus and colorectal cancer predisposition

Abstract

The role of transforming growth factor β receptor type 1 (TGFBR1) polymorphisms, particularly a coding CGC insertion (rs11466445, TGFBR1*6A/9A) in exon 1, has been extensively investigated in regard to colorectal cancer (CRC) risk. These investigations have generated conflicting results. More recently, allele-specific expression (ASE) of TGFBR1 mRNA has been suggested as predisposing to CRC, with a relative risk of nearly 10-fold and a population attributable risk of ∼10%. Owing to the potential importance of TGFBR1 variants in CRC, we performed a comprehensive examination of tagging SNPs at and around the gene in 3,101 CRC cases and 3,334 controls of northern European ancestry. To test whether rare or subpolymorphic TGFBR1 variants were associated with CRC risk, we sequenced the gene's exons in a subset of patients. We also evaluated TGFBR1 ASE in a panel of CRC cases and controls. Overall, we found no association between TGFBR1 polymorphisms and CRC risk. The rare variant screen did not identify any changes of potentially pathogenic effects. No evidence of greater ASE in cases than controls was detected, and no haplotype around TGFBR1 could account for the ASE reported in other studies. We conclude that neither genetic variation nor ASE at TGFBR1 is likely to be a major CRC risk factor. genetic susceptibility | transforming growth factor β receptor type 1 *6A/ 9A | candidate gene | low penetrance | TGF signaling T ransforming growth factor β receptor type 1 (TGFBR1) is a serine-threonine kinase that mediates growth-inhibiting signals from TGFB1 through a complex with TGFBR2. The TGFB pathway and the related bone morphogenetic protein (BMP) pathway play important roles in the pathogenesis of colorectal cancer (CRC) and other intestinal tumors: Inactivating TGFBR2 mutations occur in CRCs with microsatellite instability (MSI) (1), germline mutations in SMAD4 and BMPR1A predispose to juvenile polyposis (2, 3), and SMAD4 is mutated in some MSInegative CRCs (4). In addition, common germline variants in the BMP pathway are associated with increased risk for CRC (5). It is therefore highly plausible that germline variation at TGFBR1 itself has effects on the risk for CRC in the general population.Considerable attention has been focused on a common TGFBR1 polymorphism (TGFBR1*6A/9A, rs11466445) in exon 1 that results in the deletion of three alanines from a stretch of nine alanines. This 9-bp deletion is located within the predicted signal sequence cleavage region. Functional studies have suggested that TGFBR1*6A responds less well than the TGFBR1*9A allele to growth inhibitory signals of TGFB1. Some studies have suggested that individuals who carry a TGFBR1*6A allele are at increased risk for cancers of several types, including CRC (6). Overall, however, evidence for the association with CRC is mixed and relatively small cohorts have been analyzed.The effects on cancer risk of other common polymorphisms and rare variants at TGFBR1 have not specifically been assessed.A second line of evidence for the importance of TGFB...

Increased Variance in Germline Allele-Specific Expression of APC Associates With Colorectal Cancer

“…However, while altered germline ASE of TGFBR1 was found to associate with CRC in two subsequent studies (22, 24), these findings were not replicated in three other studies (20, 21, 23). Important for the interpretation of our results: 1) several TGFBR1 studies focused on the analyses of mean and/or median ASE values, and it is possible that differences in these parameters do not affect risk, as our data on APC suggest; 2) ASE in TGFBR1 might be more tolerated than ASE of APC and therefore could be a less important risk factor of CRC; 3) discrepancies among TGFBR1 studies may be due to differences in study design and to the use of assays and/or samples yielding inconsistent results, as suggested by Tomsic et al (22).…”

“…Three suggested that altered germline ASE in TGFBR1 associates with colorectal cancer (CRC) (19, 22, 24) and another report indicated that ASE in BRCA1 , and to a lesser extent in BRCA2 , may affect risk of breast cancer, even in the absence of a BRCA1/2 mutation (9). However, three other reports failed to replicate the association between altered germline ASE in TGFBR1 and CRC (20, 21, 23). …”

“…For example, imbalanced germline ASE, affecting different genes, is known to be associated with familial breast cancer (9), male breast cancer (10), familial chronic lymphocytic leukemia (11), familial pancreatic cancer (12), familial adenomatous polyposis coli (FAP) (3, 7, 13, 14), hereditary non-polyposis colorectal cancer (HNPCC) (8, 15), and hereditary diffuse gastric cancer (HDGC) (16). The potential role of ASE in the more common, mostly sporadic, forms of cancer has recently received increasing attention, but the evidence supporting association, although intriguing, is still controversial (9, 17, 18, 19, 20, 21, 22, 23, 24). Four reports provided evidence that moderate degrees of germline ASE associate with sporadic cancer.…”

A haplotype of TGFBR1 is predominantly found in non-small cell lung cancer patients displaying TGFBR1 allelic-specific expression

“…Two A haplotype of TGFBR1 is predominantly found in non-small cell lung cancer patients displaying TGFBR1 allelic-specific expression subsequent studies have supported the idea that expression of allelic imbalance of cancer-related genes, including TGFBR1 and CDH1, plays an important role in carcinogenesis (20,21), albeit Carvajal-Carmona et al reported no evidence of greater ASE of TGFBR1 in CRC cases than controls (22). Collectively, elucidating the association between ASE of TGFBR1 and NSCLC may improve understanding of role of TGFBR1 in NSCLC carcinogenesis.…”

Rare genetic variants and the risk of cancer

“…Initially, this was based on candidate gene approaches, testing the hypothesis that either the discovery variant itself was disease-causing or that it was in linkage disequilibrium with the disease-causing variant. Candidate genes often produced conflicting results [1][2][3]. However, with the advent of high-throughput technology, it became possible to do genome-wide association (GWA) searches, with no a priori assumptions about mechanisms, on very large numbers of polymorphic variants and on very large cohorts of cases and controls.…”