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

Abstract

Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.

Common colorectal cancer risk variants in SMAD7 are associated with survival among prediagnostic nonsteroidal anti‐inflammatory drug users: A population‐based study of postmenopausal women

“…Additional variants of 18q21 were not available from the parent study, nor were other SNPs in the SMAD/TGFB pathway. Polymorphisms in TGFB1 , TGFBR1 , and SMAD3 , for example, have recently been linked to CRC survival (Försti et al, 2010; Slattery et al, 2011b), and a more comprehensive analysis encompassing additional genes in this pathway may lead to further insights about the roles of inflammation, growth factor signaling, and survival outcomes.…”

Modifying muscular dystrophy through transforming growth factor‐β

“…). In humans, LTBP4 SNPs have also been linked to chronic obstructive pulmonary disease (COPD) , colorectal cancer , and abdominal aortic aneurysm . The association of LTBP4 SNPs with multiple human diseases reflects the tissue distribution of LTBP4 expression.…”

Genetic variation in the transforming growth factor‐β signaling pathway and survival after diagnosis with colon and rectal cancer

“…Forsti and colleagues investigated at 9 polymorphisms in the TGF-β signaling pathway and CRC among 308 patients with CRC. 32 Those authors observed that the TGF -β RA IVS7G+24A minor allele was associated with better survival and less aggressive tumors than the more common allele. We did not observe any clear differences in the HRR based on AJCC disease stage.…”