The Association Study Of Single Nucleotide Polymorphism In Genes Of Tricarboxylic Acid Cycle Metabolic Enzymes With Prognosis Of Colorectal Cancer Patients

BackgroundColorectal cancer is the third most familiar malignant tumor leading to a major cause of cancer mortality and morbidity worldwide. Recently, increased incidence rates of CRC have been observed in regions that previously had relative lower CRC risk, especially in China The role of genetic factors in CRC occerrence and development have been attached more and more attentions. Single-nucleotide polymorphism(SNP) is the most familiar form of genetic variations in human. Up to now the SNP sites which significantly associated with the prognosis of CRC patients rarely reported. At the same time, because the SNP variations in different people and differert species, many of significent SNP loci found abroad may not be verified in the han people in China. So, seeking to more sensitive and specific SNP for the prognosis evaluation of CRC in Han race has become a urgent problem to be solved.Altered metabolism is one of the top ten characteristics of cancer, contributing to the initiation and progress of tumors.Tricarboxylic acid(TCA) cycle which occurs in mitochondria is a central metabolic pathway in the metabolism of sugars, lipids and amino acids. Succinate dehydrogenase(SDH), fumarate hydratase(FH) and isocitrate dehydrogenase(IDH) are the three key regulatory enzymes of TCA cycle. With the deepening known of the tumor related molecular mechanism to people, more and more evidence has suggested that SDH、IDH and FH mutations in TCA cycle are involved in the development of cancer, Several studies have confirmed that the growth of colon carcinoma cell line was inhibited by IDH-si RNA and significantly promote cell proliferation following IDH2-overexpressing plasmid,In addition,Cells and animal experiments have confirmed that reduced SDHB expression in CRC tissues was associated with differentiation of neoplasm, and restore express of SDHB could lead to CRC cell growth inhibition.Cohort studies also reported the SDH, IDH, FH gene mutations and direct or indirect evidence indicates which mutations are associated with occurrence and development of colorectal cancer(CRC).However, the study of the association between the above SNP loci and prognosis of CRC patients has not been carried out at home and abroad up to now. PurposeSystemically assess the correlation of functional SNP in SDH、IDH、FH genes with prognosis of CRC patients,Maybe we can supply potential tumor marker which can be used to assess prognosis of colorectal cancer. MethodsWe select CRC patients who accepted radical surgery therapy, but without any preoperative anti-tumor treatment from Tangdu Hospital and Xijing Hospital affiliated to the Fourth Military Medical University as subjects and we adopted the method of prospective cohort study. The blood samples were began to collect from May 2006, At the same time,we carried on systematic collection of clinical information and standardized follow-up. By June 2012,the cumulative collection of blood samples from CRC patients with complete clinical information was 697 cases.Then we chossed 16 functional SNPs from SDH、IDH、FH genes. The functional SNP genotyping was carried out by using Mass ARRAY platform.Combined with clinical information and follow-up data, The correlation analysis was performed beteween the prognosis of CRC patients and SNP locus. Results1.We identified 4 SNPs(rs12064957 in SDHC gene、rs4131826 in SDHC gene、rs544184 in SDHD gene 、 rs7121782 in SDHD gene) in 2 genes had significant associations with CRC death risk in the overall survival(OS) analysis and 5 SNPs(rs4131826 in SDHC gene,rs10789859、rs544184 and rs7121782 in SDHD gene,rs12071124 in FH gene)in 3 genes had significant associations with CRC recurrence risk in the recurrence-free survival(RFS) analysis.2.Further analysis indicated that unfavorable genotypes exhibited a significant cumulative effect on CRC OS and RFS in a dose-dependent manner with P for trends of 1.12 x 10-4 and 0.001, respectively.3.Moreover, survival tree analysis indicated that SNP rs4131826 in SDHC gene was the primary factor contributing to the different CRC overall survival time, and SNP rs12071124 in FH gene was the primary factor contributing to the different CRC recurrence-free survival time. ConclusionOur study suggests that genetic polymorphisms in TCA cycle metabolic enzymes might be significantly associated with clinical outcomes in Chinese population diagnosed with CRC. Further functional and validated studies are warranted to expend our results to clinical utility.