TGFBR1 variants TGFBR1*6A and Int7G24A are not associated with an increased familial colorectal cancer risk

Abstract

Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case -control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P ¼ 0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P ¼ 0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se.

Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression

“…The IVS7G+24A SNP in the TGFBR1 gene has been reported to associate with invasive breast cancer, lung cancer, kidney, and bladder carcinomas (Zhang,2005; Chen et al,2006b), but not with familial CRC in a recent Swedish study (Skoglund Lundin et al,2009). In our study, based on prospective cases from North Sweden, the A allele of IVS7G+24A in TGFBR1 had a significant protective effect on the susceptibility to CRC.…”

“…The 6A allele in the signal peptide sequence of the TGFBR1 gene has been suggested to be a susceptibility allele for CRC (Pasche et al,1999; Bian et al,2005; Xu and Pasche,2007), although more recent studies, including a meta‐analysis with 2,627 CRC cases and 3,387 controls, have excluded the association between the TGFBR1 6A allele and risk of CRC (Castillejo et al,2009; Skoglund et al, 2007,2009). In our study, the 6A allele was more common in the patients with CRC (13.8%) than in the control population (11.7%).…”

“…An explanation for this apparent discrepancy between these studies may be the selection criteria of the cases. Although we selected prospective cases from two population‐based cohorts, Skoglund Lundin et al (2009) recruited the cases from families diagnosed and counseled as familial CRC. Alternatively, the results may be due to chance, because both studies were relatively small, our study consisting of 308 cases and the one by Skoglund Lundin et al (2009) of 262 cases.…”

“…Although we selected prospective cases from two population‐based cohorts, Skoglund Lundin et al (2009) recruited the cases from families diagnosed and counseled as familial CRC. Alternatively, the results may be due to chance, because both studies were relatively small, our study consisting of 308 cases and the one by Skoglund Lundin et al (2009) of 262 cases. According to the HapMap, the IVS7G +24A SNP captures 32 of 35 common SNPs (MAF ≥ 10%) with r 2 > 0.8 in the TGFBR1 gene.…”

The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

“…Individuals carrying the Int7G24A variant have an increased risk of developing non-small cell lung cancer, renal cell carcinomas, transitional cell carcinomas of the bladder, and breast cancer [ 7 - 10 ]. To our knowledge, there is only one published report on the association between this genetic variant and CRC [ 11 ]. In that study, there was no evidence of an association between this polymorphism and colorectal cancer risk in familial cases.…”