Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk

Abstract

Interaction of TCF7l2 with translocated β-catenin in the nucleus transiently converts TCF7L2 to transcription factor activators, which induce the expression of target genes, including cyclin D1 and c-myc, in colorectal carcinogenesis. We evaluated the association of a polymorphism in TCF7L2 (RS12255372) which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. In the NHS and HPFS control populations, the TCF7L2 T-allele frequency ranged from 28 to 30% and the genotype distribution was in agreement with Hardy-Weinberg equilibrium. Overall, there was suggestive evidence for an inverse association associated with homozygosity for the minor allele of RS12255372 (TCF7L2 TT) and CRC (conditional and covariate adjusted OR=0.63, 95%CI: 0.37-1.08; P for heterogeneity 0.52 for the association in women and men), which was more evident among women (OR=0.39, 95%CI: 0.16 -0.91). The polymorphism was not associated with risk of colorectal adenoma. Furthermore, we observed no evidence of effect modification between the TCF7L2 SNP and covariates such as family history or with genetic variants in the APC Asp1822Val SNP (NHS cancer p-interaction=0.40, NHS adenoma p-interaction 0.10). In summary, the marginal association of TCF7L2 SNP with CRC may be due to chance, but warrants further laboratory and epidemiological investigation.

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…(iii) Finally, a Kaplan–Meier survival analysis further narrowed down this list to 177 candidate tumor suppressors whose downregulation is negatively correlated with patient survival (and thus, likely to enhance tumor progression; see Materials and Methods, Fig 1A and Table EV3). Reassuringly, the resulting list includes several known colon tumor suppressors such as APC (Fearnhead et al , 2001; Aoki & Taketo, 2007), TCF7L2 (Hazra et al , 2008; Slattery et al , 2008), MCC (Kinzler et al , 1991), PTEN (Nassif et al , 2004; Song et al , 2012), and SMAD4 (Miyaki et al , 1999; Alazzouzi et al , 2005). It also includes 34 metabolic genes that are present in the human metabolic model (Table EV4), and which we further studied in the next modeling step.…”

Association of common polymorphisms in IL10, and in other genes related to inflammatory response and obesity with colorectal cancer

“…Association of nuclear β-catenin with this transcription factor promotes the expression of several compounds that have important roles in the development and progression of colorectal cancer (e.g., c-myc, cyclin D1) [50]. The T allele of this SNP was statistically significantly positively associated with colon cancer risk in a nested case–control study in the Atherosclerosis Risk in Communities study [13], no overall association was observed in a population-based case–control study but a significant interaction by aspirin/NSAID use was observed (positive association among not recent aspirin/NSAID users) [51], and an inverse association was seen in a third study conducted in the Nurses’ Health Study and the Health Professionals Follow-up Study that evaluated the association between the rs12255372 SNP (in linkage disequilibrium with the rs7903146 SNP) [52]. …”

Inference of hierarchical regulatory network of TCF7L2 binding sites in MCF7 cell line

“…Several studies have found that TCF7L2 can be either an activator or a repressor, depending on the availability of CTNNB1 in the nucleus (Shitashige et al, 2008; Clevers, 2006; Daniels and Weis, 2005). It is now clear that TCF7L2 is linked to a variety of human diseases including different types of cancers, such as colon, liver, breast, and pancreatic cancers (Poy et al, 2001; Prokunina-Olsson et al, 2009; El-Tanani et al, 2008; Roose and Clevers, 1999; Slattery et al, 2008; Hazra et al, 2008; Van De Wetering et al, 2002). In addition, alternative splicing variants in TCF7L2 genes are thought to be the most critical risk factors for type 2 diabetes (Cauchi and Froguel, 2008; Voight et al, 2010; Grant et al, 2006; Weedon, 2007).…”