| Backgrounds and ObjectivesColorectal cancer is one of the most common gastrointestinal malignancies, which is considered as the three of the most commonly diagnosed cancers worldwide with breast cancer and lung cancer. It’s estimated that global new case of CRC would reach to1.2million in2007, and raise by3.9%every year. Incidence of CRC tends to be low in China. But the incidence and mortality are increasing rather rapidly with the development of economy and change of life style in the past decades, which have been even higher than some westen countries as the USA. CRC has become a global public health problem as it has threaten the quality of people’s life and aggravated the social burden seriously. Early treatment of colorectal cancer could get better effect, so further research of colorectal cancer pathogenesis to improve screening technology, find out and treat cancerization earlier is meaningful to increase the survival rate of colorectal cancer.Colorectal carcinogenesis is a multfactories、mnultsteps and long-term process. The susceptibility of disease in individual is different even in the same enviroment, which suggests that genetic factories play a potential role in carcinogenesis. As is know, the activation of oncogenes and inactivation of tumor suppressor genes are involved in gene regulation. Now, many genes have been reported to be closely related to the colorectal carcinogenesis. It’s found that the expression of insulin-like growth factor binding protein7may be associated with colorectal cancer recently.IGFBP7belongs to the IGFBPs superfamily and plays biological effect through IGF axis. IGFBPs bind to the IGFs prior, which inhibit the binding of IGFs and its receptor to regulate cell proliferation, cell adhesion, apoptosis, cellular senescence and angiogenesis. Studies suggest that IGFBP7may play a role in the development of malignant tumor, but the mechanisms may be different in different cancers. The expression of IGFBP7is lower than normal tissue in many cancer types, such as cancers of breast, lung, stomach, melanoma and leukemia. Paradoxically, IGFBP7expresses higher in pancreatic and glioma cancer cells. But the expession of IGFBP7in colorectal and prostate cancer are conflicting.The mechanism of abnormal expression of IGFBP7is still unclear. It may be related to regulation of gene expression. Genetic variance plays an important role in gene regulation by nucleotide sequence change, in which single nucleotide polymorphism(SNP) is the hotspot.199SNPs have been reported in the upper3000bp and backward3000bp of IGFBP7in the NCBI SNP database. To date, only one study reported the association of IGFBP7SNPs and head and neck cancer, suggested the genetic variance in promoter region may affect the expression of IGFBP7and further influence the tumor susceptibility. But the relationship of IGFBP7genetic variance and colorectal cancer has not been reported yet.A case-control study was conducted to screening IGFBP7SNPs related to colorectal cancer by a high-throughput SNPs detection of Genome Wide Association Study (GWAS) in this study. We want to evaluate the association between polymorphisms of IGFBP7and colorectal cancer risk, find out new biomarkers for CRC screening and diagnose and provide theory for prevention and treatment.Material and MethodsWe conducted a case-control study of925CRC patients and939cancer-free controls. Cases were collected from the first affiliated hospital of Zhejiang University, ShaoYi-fu hospital, Taizhou hospital and Jiashan country. Whole blood or tissue samples of all patients were collected as well as information of demographic characteristics including age and gender after informed consent. Controls were chosen from database of Metabolic syndrom in Xiaoshan. The subjects recruited must had the whole blood samples as well as information of age,gender and history of tumors. The genomic DNA was extracted from peripheral blood or tissue samples by kits and GWAS were performed by chip technology to determine47TagSNPs of IGFBP7. The Hardy-Weinberg equilibrium in controls was tested by PLINK. Statistical analysis was performed by SPSS16.0. The distribution of genotypes between cases and controls were tested by χ2test. Logistic regression was used to calculate the risk of SNPs and CRC by odds ratios(ORs) with95%confidence intervals(95%CI) after adjusting age and gender. Interaction and joint action of positive SNPs were formally assessed by mult-factories logistic regress after adjusting age and gender. Haplotype analyses of these polymorphisms were performed using Haploview and R software. All tests were two-sided and p<0.05were considered as statistical significantly.ResultsThe polymorphisms of rs1277308, rs11133472, rs7656865, rs1718848and rs1277311were related to coloretal cancer risk(p=0.045, p=0.011, p=0.047, p=0.029'p=0.030). When the wild genotype was used as the reference, an increase risk of CRC was significantly associated with rs11133472AG genotype(OR=2.39), rs7656865CT genotype (OR=2.11) and rs1718848AG genotype(OR=2.37) after the adjustment of age and gender. The mutations of the three SNPs were low frequency and high effect with no mutative homozygous genotypes and high ORs. However, rs1277308TT/CT genotype and rs1277311CT genotype could reduce the risk of CRC compared with other genotypes(OR=0.83and OR=0.81).There were no interactions among rs11133472、rs7656865and rs1718848, but joint effects between rs11133472AG and rs1718848CT genotype, rs7656865CT and rs1718848AG genotype, rs11133472AG and rs1718848AG genotype increased colorectal cancer risk with the ORs were2.43(95%CI:1.29-4.57),2.44(95%CI:1.27-4.68) and2.57(95%CI:1.29-5.16). Joint effect between rs1277308TT/CT and rs1277311CT genotype, reduced colorectal cancer risk with the OR was0.68(95%CI:0.52-0.89).There were9haplotypes for the47SNPs in IGFBP7. The distribution of combinations of alleles were different in the7th haplotype (p=0.036).But there were no significance between two combinations.ConclusionsFive IGFBP7SNPs were found to be related to CRC risk. The carriers of rs11133472AG, rs7656865CT and rs1718848AG genotype showed a two-fold increase CRC risk. Joint action of the three SNPs raised the risk more. However, rs1277308TT/CT genotype and rs1277311CT genotype could reduce the risk of CRC. In summary, the five SNPs may be meaningful biomarkers for CRC genetic susceptibility. |
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