Association of SNP in phospholipase A2 gene with prostate cancer

Phospholipase A2 (PLA2) are lipolytic enzymes that hydrolase membrane phospholipids to form biologically active fatty acids like Arachidonic Acid (AA) and lysophospholipids, which in turn regulates important cellular events including inflammation, immunity, tumorigenesis and metastasis. Secretory Phospholipase A2-IIA (sPLA2-IIA) is a Ca2+ dependent hydrolase within same family of enzymes, which was shown to be elevated in several malignancies, including prostate cancer (PCa). High level of sPLA2-IIA was correlated with high prostate tumor grade and tumor proliferation in primary site tumors. Furthermore, the high serum level of enzyme in association with high Gleason score and advanced disease stage suggests sPLA2-IIA as a biomarker for poor prognosis of PCa. Aim of this thesis was to reveal first time the association of 5'UTR polymorphism (rs11573156) with PCa and survey the effects of possibly harming two additional polymorphisms (rs374105365 and rs965800220) with computational simulation analysis. Genotype analysis of patients and control group was performed with PCR-RFLP analysis by using isolated DNA samples. Short molecular dynamics simulations (md) were performed on native and mutated protein structures, designed with homology modeling where quality assessments were performed according to their Ramachandran plots. According to our results, heterozygous genotype (CG) for rs11573156 polymorphism is significantly associated with reduced metastatic incidence of PCa in Turkish population while showing no significant association with PCa susceptibility. Computational analysis results demonstrated that remaining two polymorphisms do not directly alters active site interactions. However, surface electrostatic change may have indirect effect how PLA2G2A exert its effect but it needs further investigation on residues that interacts with membranes or lipid surfaces.