The Association Study Of Single Nucleotide Polymorphism In The Tumor Growth And Regulation Related Genes With Prognosis Of Colorectal Cancer Patients

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in China. In recent years, with the improvement of people’s living standard and the change of dietary structure, the incidence of CRC is increasing year by year, and because of the hidden onset, rapid progress, high mortality, CRC has become a public health problem of China, which seriously harm people’s health. Genetic factors in tumor genesis and development have attached more and more attentions. Single-nucleotide polymorphism (SNP) is one of the most common genetic variations in human. SNP can reflect the genetic background of people, and it has many advantages such as rapid and convenient detection, so it will be helpful for evaluation of risk and prognosis of tumor. So far the SNP sites which significantly related with the prognosis of CRC patients are very few, and because of the SNP variations among different races and different nations, many of SNP found abroad can’t be verified in Han population. Therefore, finding more specific, sensitive SNP sites for the prognosis assessment of CRC in Han population has become current issue that need to be resolved.It has reported that circadian genes, integrin family and VEGF family all belong to tumor growth and regulation related genes. They play important role in the development and progression of human cancers. The protein products of CLOCK, NPAS2 and BMAL1 form cis acting elements, and drive the circadian rhythm. Also they can influence cell apoptosis, cell cycle regulation, DNA damage repair and other important function through regulating downstream genes such as P53 and so on. Studies have shown that the expression level of beta-1 integrin is closely related with the differentiation degree and metastasis of CRC patients. VEGF, which is the most important gene in VEGF family, is over-expression in CRC tissue, and the expression level is associated with malignant degree, metastasis, micro vascular density and prognosis of tumor. These genes play important role in tumor genesis and development. However, whether their functional SNPs have any influence on CRC clinical outcomes remains unclear.Purpose: The association of functional SNP in CLOCK, NPAS2, BMAL1, ITGB1 and VEGF with prognosis of CRC patients. Maybe we can provide new tumor marker which can be used to evaluate CRC prognosis in Han population.Methods: We chose CRC patients who received retreatment in our department as a sample of CRC patients in northwest in China and we designed a prospective study. The blood samples were began to collect from 2008, and clinical informations of each patient was collected too. Then we did standard follow-up and finally 411 blood samples with complete information were collected until October 2010. After that we selected 18 functional SNPs from CLOCK, NPAS2, BMAL1, ITGB1 and VEGF genes. SNP genotyping was performed using MassARRAY platform which based on MALDI-TOF mass spectrometry technology. Then we did statistics analysis with epidemiological data, clinical data and follow-up data to find the association of SNP with clinical outcome of CRC patients.Results: First we found that patients carrying the homozygous variant and heterozygous variant genotype of rs3749474 or heterozygous variant of rs1801260 had a significantly increased overall survival than those carrying other genotypes (HR = 0.55, P = 0.003 and HR = 0.31, P = 0.03, respectively). Compared with patients carrying 0 unfavorable genotype, those carrying 2 unfavorable genotypes had a 2.92-fold increase of death risk (HR = 2.92, P = 0.03). Second we found that the death risk conferred by rs2230395 remained significant in patients receiving chemotherapy (HR = 2.69, P = 0.008), and death risk conferred by rs1187075 remained significant in patients receiving chemotherapy (HR = 2.38, P = 0.01).Conclusion: This is the first study to analysis the association of function SNP from CLOCK, NPAS2, BMAL1, ITGB1 and VEGF genes with prognosis of CRC patients. We found that two SNPs (rs3749474 and rs1801260) in CLOCK gene were significantly associated with CRC overall survival, and two SNPs (rs2230395 and rs1187075) in ITGB1 gene were significantly associated with overall survival in CRC patients receiving chemotherapy. The results of our study can be evidences for further study of CLOCK and ITGB1 in CRC genesis and development, and these SNP may be provided as prognostic marker for CRC patients.