The Single Nucleotide Polymorphism (rs4963) In ADD1is Associated With Susceptibility To Gastric Cancer And Liver Cancer

Phosphorylation can alter the function and activity of many proteins, thereby governs complicate cellular activities, such as cell proliferation, growth, differentiation and apoptosis. ADD1is a component of cytoskeleton. It takes part in the assembly of actin and promotes the association of spectrin with actin, thus plays a role in cell proliferation, motility and cell-cell junctions. Recently, most of studies focus on somatic mutations influence the phosphorylation status, few studies is reported about the effect of genetic variant in the phosphorylation site. In this study, we investigated the associations between missense SNP in the codon of phosphorylation site and the development of cancers using candidate genes strategy.Combining the information of dbSNP and PhosphoSitePlus database, we identified the missense SNP in the codon of phosphorylation site of ADD1, located on chromosome4p16.3:ADD1S586C(rs4963C>G). The rs4963G allele is in the codon that codes cysteine which cannot be phosphorylated. Genotyped by TaqMan, we conducted association study that included1998cases with non-cardia gastric cancer and2008cancer-free controls. Analysis was conducted by using logistic model adjusted by gender and age. The rs4963was significantly associated with susceptibility to non-cardia gastric cancer. Compared with CC genotype, the rs4963CG genotype and GG genotype significantly increased the risk of non-cardia gastric cancer (OR=1.24,95%CI:1.06-1.46, P=0.008) and (OR=1.49,95%CI:1.25-1.78, P=1.20×10-5), respectively. The association between rs4963and survival of non-cardia gastric cancer was analyzed in the group including723patients. Multivariate Cox regression analysis showed rs4963was not an independent prognostic factor for non-cardia gastric cancer patients and Kaplan-Meier analysis showed no differences in survival among different genotype patients.To further investigate the association between rs4963and susceptibility to multiple cancer, we conducted case-control analyses of2588individuals with esophageal squamous-cell cancer,1873individuals with liver cancer,1083individuals with pancreatic cancer and4183controls. We found the rs4963was significantly associated with susceptibility to liver cancer. Compared with CC genotype, the rs4963GG genotype significantly increased the risk of liver cancer (OR=1.21,95%CI:1.03-1.43, P=0.019). However, rs4963was neither associated with susceptibility to esophageal squamous-cell cancer nor associated with susceptibility to pancreatic cancer. Combing data of four types of cancer and all controls showed this genetic variant was associated with susceptibility to cancer:compared with CC genotype, the rs4963GG genotype significantly increased the risk of cancer (OR=1.20,95%CI:1.07-1.35,P=0.002).In conclusion, Our results demonstrated for the first time that rs4963in ADD1might be a genetic susceptibility factor to non-cardia gastric cancer and liver cancer. This genetic variant might alter the phosphorylation status of ADD1and influence ADD1’s function.