Genetic Polymorphisms in MMP9 and COX2 Gene and Risk for ...

[Abstract]

ObjectiveWorldwide, gastric cancer is the third cause of cancer-related death. The disease is most common in China. Studies on the development of gastric cancer suggest that genetic predisposition, infection, and diet are part of a complex interaction.Single nucleotide polymorphisms (SNPs) are thought to be the genetic basis of most human diseases, or at least positional markers for our genetic heritage. Recent studies show that low-penetrance disease susceptibility genes, which are relatively common in the population, may confer a much higher attributable risk in the general population than rare mutations in high-penetrance disease susceptibility genes. In the last several years, attention in the human genetics community has increasingly turned from the study of single-gene, Mendelian disorders to the search for DNA sequence variants associated with increased risks for the developed of common, or complex diseases caused by the interaction of hereditary and environmental influences. The great majority of SNPs are not associated with changes in gene structure or function, but a small proportion are believed to be directly responsible for genetic disease. One of the central challenges of modern human genetics is to identify these deleterious SNPs. Studies to investigate the role of SNPs in genetic susceptibility to human diseases will offer the possibility of designing novel targeted therapies in the future.Matrix metalloproteinases are a closely related multigene family of zinc-dependent proteolytic enzymes. They have a role in normal physiological tissue remodelling and are capable of degrading all components of the extracellular matrix. There is increasing evidence that metalloproteinases play many important roles in cancer, for example, releasing and activating growth factors and other proteases and assisting tumour cells to invade the extracellular matrix. In addition, MMPs potentiate neovascularisation of tumour tissue, with MMP9 expression being correlated with angiogenesis in colorectal cancer. Cyclooxygenases (COX)1 and 2 are the key enzymes in the conversion of arachidonic acid to prostaglandins. COX2 appears to play an emerging role in inflammation and carcinogenesis. Polymorphisms in the C0X2 gene could alter enzyme expression.This study aimed at investigating genetic polymorphisms of MMP9 and C0X2 gene, and the contribution of MMP9 and C0X2 polymorphisms to the risk of gastric cancer in Chinese.Materials and MethodsUnrelated subjects from Shenyang of China were enrolled for case-control studies of risk factors for CRC. The trial recruited 137 CRC patients and 199 healthy control subjects. Cases were patients with a histologically confirmed new diagnosis of CRC in the First Affiliated Hospital of China Medical University and Shenyang Anal Hospital, between 2005 and 2006. CRC patients were 71 men and 66 women; the median age was 61.29 years. CRC patients were grouped according to TNM-classification (UICC), on the basis of the postoperative histopathology evaluation.Controls were randomly selected among the people admitted to the same hospital during the same period. Control subjects were 104 men and 95 women; the median age was 60.65 years. These control subjects had no history of cancer.All subjects were consent to participate in the study, and allow their blood samples to be analyzed. Detailed information on risk factors including tobacco, alcohol, BMI (This study used the suggested WHO BMI cutoff points for Asians to assess several variables, respondents whose BMI was less than 23kg/m~2 were categorized as normal weight, and respondents whose BMI was 23kg/m~2 or higher were categorized as overweight and obese) were obtained with a baseline questionnaire.The polymorphisms were detected by PCR-RFLP (polymerase chain reaction ? restriction fragment length polymorphism). Odds ratio (OR) and 95% confidence interval (CI) were estimated by logistic regression analyses from comparison of genotypes between CRC patients and healthy controls using SPSS version 13.0.Results1. MMP9 polymorphisms and risk for colorectal cancerThe frequencies of MMP9-1562C>T and 279R>Q genotypes was not statistical different between cases and controls (-1562CT+TT vs CC: OR=0.877, 95%CI=0.527-1.462, P=0.615; 279RQ vs QQ: OR=0.936, 95%CI=0.410-2.138, P =0.875; RR vs QQ: OR=0.961, 95%CI =0.424-2.177, P=0.924). Furthermore, we estimated the association between the -1562C>T and 279R>Q genotypes and clinicopathological among CRC patients. Logistic regression analysis revealed that CRC patients with -1562CT+TT genotype showed increased risk of lymph node metastasis(CT+TT vs CC: P=0.022). The frequency of MMP9 279RR+RQ genotype is higher than the QQ genotype among the CRC patients who is younger than sixty years old.2. COX2 polymorphisms and risk for colorectal cancerRisk associated with the COX2-765G>C variant differed by smoking and BMI. There was a positive association between cigarette smoking and development of CRC in the study population. The -765GG genotype in smokers, were associated with a relative increased risk of colorectal cancer compared to never smokers (OR=2.682, 95%CI=1.336-5.385, P=0.006). The intake of alcohol was not positive for CRC development in this study. The effect of -765GG genotypes on CRC development were observed when individuals were stratified by BMI status. Compared to those with a normal BMI (18.5-22.9), those overweight (BMI 23-24.9) had a 3.909 fold increase in risk of CRC (OR=3.909, 95%CI= 2.081-7.344, P25) had a 2.031 fold increase in risk of CRC (OR=1.107, 95%CI=1.107-3.726, P=0.022).Conclusions 1. Our results indicate that MMP9-1562OT polymorphism has influence on the Lymph node metastasis of CRC. And MMP9 279R allele may lead to a younger age of onset of colorectal cancer.2. Although C0X2 -765G>C polymorphism are not associated with an increased risk of CRC, -765GG genotype appear to be associated with an increased risk in the presence of smoking and higher BMI.

Title: Genetic Polymorphisms in MMP9 and COX2 Gene and Risk for Colorectal Cancer

Category: Tumor Biol

Filename: Genetic Polymorphisms in MMP9 and COX2 Gene and Risk for Colorectal Cancer.pdf

Pages: 138

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