Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects mismatches generated during DNA replication. MMR defects were found to be associated with hereditary non-polyposis colorectal cancer (HNPCC) and a subset of sporadic colon cancers. The inheritance of common variations in MMR genes may influences individual susceptibility to the development of colorectal cancer. The purpose of the study was to evaluate the association between gene polymorphisms Glu39Gly (c.116G > A) of MSH6 gene and IVS1-1121C > T of PMS2 gene and sporadic colorectal cancer risk, in a case-control study comprising 200 patients and 200 controls origination from polish population. DNA was isolated from peripheral blood lymphocytes of enrolled patients, and gene polymorphisms were analysed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) for MSH6 and TaqMan for PMS2. G/A variant of Glu39Gly (c.116G > A) genotype was associated with an increased risk of colorectal cancer (OR 1,65 95%CI:1,01–2,69 p = 0.44). Presence of A allele was also significantly higher in patient with CRC (OR 1,57 95% CI: 1,04–2,38 p = 0.032). Prevalence of this genotype was also markedly higher in females and patients above 60 years in CRC group (OR 2.25 95%CI: 1.22–4.14 p = 0.0098 and OR 2.74 95% CI: 1.27–5.93 p = 0.0097 respectively). None of such correlations was observed for genotype variants of IVS1-1121C > T PMS2. In conclusion, our data suggests thatMSH6 Glu39Gly polymorphism is associated with the risk of developing sporadic colorectal cancer in polish population. Linkage to the female gender, onset above 60 years old and further increase of risk when combined with wild-type allele of PMS2 IVS1-1121C > T polymorphism indicates defective mismatch repair system.
Highlights
Colorectal cancer (CRC) is the third most common cancer in the world, with nearly 1.4 million new cases diagnosed in 2012 [1]
Deficient mismatch repair (MMR) system resulting in high-microsatellite instability (MSI) accounts for 15% of CRCs with 3% being associated with hereditary nonpolyposis colorectal carcinoma (HNPCC), and the 12% with sporadic cancer [6], but low-MSI status is often noted in group of tumours originating from other pathways [3, 7]
Over the past few years, there is more and more evidence that CRC is a very heterogeneous disease and that numerous molecular and genetic features may contribute to its development and prognosis, which is especially evident in sporadic colorectal cancer [3, 9, 19]
Summary
Colorectal cancer (CRC) is the third most common cancer in the world, with nearly 1.4 million new cases diagnosed in 2012 [1]. Deficient MMR system resulting in high-MSI accounts for 15% of CRCs with 3% being associated with hereditary nonpolyposis colorectal carcinoma (HNPCC), and the 12% with sporadic cancer [6], but low-MSI status is often noted in group of tumours originating from other pathways [3, 7] This indicates that MSI status may be involved in significantly larger number of CRC cases than those confined only to MSI-H phenotype. Authors emphasized its sensitivity in detecting MMR deficient cases, including those in which complete loss of MMR system was not present These reports prompted us to investigate if common polymorphisms of MSH6 and PMS2 genes of MMR system modulate the susceptibility to sporadic colorectal cancer development in population of our region, including potential combine effect of these polymorphisms on risk of CRC development
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