Background/Aim: The aim of this study was to analyse the genetic profiles of metastatic castrationresistant prostate cancer (mCRPC) by using next generation sequencing to identify variants with pathogenic potential in nine DNA repair genes-BRCA1, BRCA2, RAD50, RAD51, RAD51C/D, ATM and ATR. Materials and Methods: Isolated genomic DNA from peripheral blood of 50 patients with mCRPC was used for the sequencing of 111 genes associated with hereditary cancer on an Illumina platform. Identified variants were tested in Integrative Genomic Viewer, their clinical significance confirmed in databases and their potential impact on protein function predicted by in silico tools. Results: From nine analysed DNA repair genes, we identified 14 relevant variants; three pathogenic variants-BRCA2 (rs80359306), RAD50 (rs786201531) and ATM (rs1555099760), and eleven other variants with pathogenic potential. Conclusion: The pathogenic variants identified in this study are located in evolutionarily conserved regions of proteins and are highly likely to affect DNA repair efficiency.
Background/Aim: Our aim was to investigate possible influences of genetic variants in genes involved in the G 1 /S transition , cyclin E1 (CCNE1) and cyclin-dependent kinase inhibitor 1B (p27 KIP1 )] on the expression/activity of their corresponding proteins and to assess the functional impact of these variants on the risk of prostate cancer. Materials and Methods: We genotyped 530 cases and 562 healthy controls for two relevant single nucleotide polymorphisms (CDK2 rs2069408 and CCNE1 rs997669) by TaqMan genotyping assay. p27 KIP1 rs2066827 polymorphisms were studied by polymerase chain reactionrestriction fragment length polymorphism assay. In addition, the expression of CDK2, CCNE1 and p27 KIP1 was evaluated by quantitative real-time-polymerase chain reaction and western blotting in 44 prostate cancer tissues and 31 benign prostatic hyperplasia tissues. Results: No association was found between CDK2 rs2069408, CCNE1 rs997669 or p27 KIP1 rs2066827 polymorphisms and an increased risk of prostate cancer development. Higher CDK2 expression was more prevalent in those with rs2069408 GG genotype than in AA carriers (p>0.05). We also noted reduced p27 KIP1 protein expression in those with the p27 KIP1 G109 allele. No difference was observed for CCNE1 expression in relation to the risky genotype (CC). A significant association was detected between CCNE1 mRNA overexpression and development of higher-grade carcinomas (Gleason score >7, p<0.05). Conclusion: Polymorphisms CDK2 rs2069408, CCNE1 rs997669 and p27 KIP1 rs2066827 have no significant impact on prostate cancer risk nor on the gene and protein expression of CDK2, CCNE1 and p27 KIP1 , although high CCNE1 expression was significantly associated with a higher tumour grade in patients with prostate cancer.
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