Association between MLH1 -93G>A Polymorphism and Risk of Colorectal Cancer

Abstract

BackgroundThe -93G>A (rs1800734) polymorphism located in the promoter of mismatch repair gene, MLH1, has been identified as a low-penetrance variant for cancer risk. Many published studies have evaluated the association between the MLH1 -93G>A polymorphism and colorectal cancer (CRC) risk. However, the results remain conflicting rather than conclusive.ObjectiveThe aim of this study was to assess the association between the MLH1 -93G>A polymorphism and the risk of CRC.MethodsTo derive a more precise estimation of the association, a meta-analysis of six studies (17,791 cases and 13,782 controls) was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. Four of these published studies were performed on subjects of known microsatellite instability (MSI) status. An additional analysis including 742 cases and 10,895 controls was used to assess the association between the MLH1 -93G>A polymorphism and the risk of MSI-CRC.ResultsThe overall results indicated that the variant genotypes were associated with a significantly increased risk of CRC (AG versus GG: OR = 1.06, 95% CI = 1.01–1.11; AA/AG versus GG: OR = 1.06, 95% CI = 1.01–1.11). This increased risk was also found during stratified analysis of MSI status (AA versus GG: OR = 2.52, 95% CI = 1.94–3.28; AG versus GG: OR = 1.29, 95% CI = 1.10–1.52; AA/AG versus GG: OR = 1.45, 95% CI = 1.24–1.68; AA versus AG/GG: OR = 2.29, 95% CI = 1.78–2.96). Egger’s test did not show any evidence of publication bias.ConclusionOur results suggest that the MLH1 -93G>A polymorphism may contribute to individual susceptibility to CRC and act as a risk factor for MSI-CRC.

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

“…38 Rs1800734 encodes for a G to A transition at −93 from the transcription start site within the promoter region and it falls within NF-IL6 and GT-IIB transcription factor binding sites. The polymorphism has been associated with promoter methylation and gene silencing 39,40 and a meta-analysis by Wang et al 41 reported that carriers of the A-allele are at increased risk of colorectal cancer, in agreement with the present results. The association was even stronger among cases positive for MSI.…”

Recent evidence on modifiable and non-modifiable risk factors for colorectal cancer (CRC): a systematic synopsis of meta-analyses from 2015 to 2017

“…30,31 The most prominent result of genetic studies is the role of mutation in Lynch syndrome (MSH2 and MLH1) and the future development of CRC from previous studies. 32,33 The increased risk for the XRCC1 and BMP4 gene mutations is comparable with a previous review. 34,35 The role of a genetic mutation in the 8q23.3 and 15q13.3 loci is a novel finding that might need future research.…”

Association between MutL homolog 1 polymorphisms and the risk of colorectal cancer: a meta-analysis

“…Compared with the similar metaanalysis about MLH1 c. -93G>A polymorphism and CRC, it is the one comprising most studies and consisting of largest population, and the results tended to be more exact and reliable. In 2012, Wang et al (2012) reported that MLH1 c. -93G>A polymorphism was related to increased risk of CRC. However, they only involved six studies, and the ethnicity was just European and Americans.…”

“…Additionally, Wang et al (2012) concluded that the MLH1 -93G>A substitution altered promoter function, reduced MMR system activity and was associated with increased risk of CRC. However, Pan et al (2011) could not offer persuasive evidence that allele A was a risk factor for CRC.…”