Abstract
Cumulative evidence suggests that MLH1, the key component in the mismatch pathway, plays an important role in human cancers. Two potential functional polymorphisms (-93G>A and I219V) of MLH1 have been implicated in cancer risk. The aim of this meta-analysis was to summarize the evidence for associations. Eligible studies were identified by searching the electronic literature PubMed, ScienceDirect and Embase databases for relevant reports and bibliographies. Studies were included if of case-control design investigating MLH1 polymorphisms (-93G>A and I219V) and cancer risk with sufficient raw data for analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to evaluate the strength of associations. Our meta-analysis from 33 published case-control studies showed the variant A allele of -93G>A polymorphism to be associated with increased risk in all genetic models (AA vs. GG: OR = 1.22, 95% CI: 1.03-1.44), especially among non-Asians (AA vs. GG: OR = 1.28, 95% CI: 1.04-1.58). For the I219V polymorphism, however, there was no main effect associated with overall cancer risk in any genetic model. The meta-analysis suggested that the MLH1 -93G>A polymorphism may be a biomarker of cancer susceptibility. Large sample association studies and assessment of gene-to-gene as well as gene-to-environment interactions are required to confirm these findings.
Highlights
Exogenous carcinogens and endogenous oxygen species can induce DNA damage and genomic instability that may lead to carcinogenesis (Barnes, 2002)
The meta-analysis suggested that the MLH1 -93G>A polymorphism may be a biomarker of cancer susceptibility
MLH1 Polymorphisms and Cancer risk: a Meta-analysis Based on 33 Case-control Studies Table 1
Summary
Exogenous carcinogens and endogenous oxygen species can induce DNA damage and genomic instability that may lead to carcinogenesis (Barnes, 2002). There are several major DNA repair pathways which are expected to play a role in maintaining genomic stability (Bernstein et al, 2002), including nucleotide excision repair (NER), base excision repair (BER) and DNA double strand breaks (DSBs). The mismatch repair (MMR) pathway, first described in bacteria, is a highly conserved process which is responsible for recognizing and correcting DNA base pairing errors in newly replicated DNA (Harfe and Jinks-Robertson, 2000). It has been confirmed that double-strand break repair is modulated by MMR (Jacob and Praz, 2002). MMR defective cell lines display various forms of genomic instability (Surtees et al, 2004). Animal experiments in mice indicate that MMR gene deficiencies lead to an increased level of microsatellite instability (MSI) and susceptibility to cancer (Ellison et al, 2004). Dysfunction of MMR can be one of possible genetic risk factors in cancer etiology
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