Studija asocijacije genetičkih varijanti u regionima 7q36, 8q24 i 17q12 sa rizikom za razvoj i progresiju karcinoma prostate

Abstract

Karcinom prostate je drugi najčešće dijagnostikovan maligni tumor muškaraca u svetu, i šesti po broju smrtnih slučajeva. Standardni dijagnostički i prognostički parametri KP su serumska vrednost prostata specifičnog antigena (PSA), Glison gradus sistem (GGS), i klinički stadijum KP. Studije asocijacije na čitavom genomu identifikovale su preko 30 SNP asociranih sa rizikom za razvoj i progresiju KP. Genetičke varijante predstavljaju potencijalne genetičke markere koji bi se pored standardnih prognostičkih parametara koristili u dijagnostici i praćenju bolesnika sa KP. Rezultati replikativnih studija slučajeva i kontrola potvrdili su da pojedinačne genetičke varijante mogu imati različit stepen asocijacije sa rizikom za razvoj i/ili progresiju KP u različitim populacijama. Ova studija imala je za cilj da proceni moguću asocijaciju genotipova i alela genetičkih varijanti u regionu 7q36 (rs1799983, rs2070744, NOS3 -764A>G, NOS3 - 714G>T, rs3918226, NOS3 -649G>A), regionu 8q24 (rs1447295, rs4242382, rs6983267, rs7017300, rs7837688) i regionu 17q12 (rs3760511, rs7501939) sa rizikom za razvoj i progresiju KP. Studija je obuhvatala 150 bolesnika sa KP, 150 bolesnika sa benignom hiperplazijom prostate (BPH) i 100 muškaraca bez kliničkih znakova bolesti prostate (kontrolna grupa). Genotipizacija genetičkih varijanti vršena je metodom RFLP i metodom automatskog sekvenciranja. Za svih pet SNP u regionu 8q24 (rs1447295, rs4242382, rs6983267, rs7017300 i rs7837688), kao i za rs7501939 iz regiona 17q12 pokazana je asocijacija sa rizikom za razvoj KP. U našoj studiji, od 13 analiziranih genetičkih varijanti, za samo dve, rs3760511 (region 17q12) i rs1799983 (region 7q36), pokazana je asocijacija sa standarnim prognostičkim parametrima KP. Rezultati naše studije pokazali su asocijaciju genetičkih varijanti rs3760511 (region 17q12) i rs3198266 (region 7q36) sa rizikom za progresiju KP...

Prostate cancer (PCa) is the second most frequently diagnosed malignant tumor, and the sixth leading cause of cancer-related deaths among men worldwide. Standard diagnostic and prognostic parameters are serum PSA level, Gleason gradus score, and the clinical stage of PCa. Genome-wide association studies (GWAS) have identified over 30 single nucleotide polymorphisms (SNPs) associated with human PCa. Genetic variants have emerged as potential genetic markers that could be used along with standard prognostic parameters in PCa diagnostics and outcome prediction. This study aimed to evaluate possible association between genotypes and alleles of genetic variants at 7q36 (rs1799983, rs2070744, NOS3 -764A>G, NOS3 -714G>T, rs3918226, and NOS3 -649G>A), 8q24 (rs1447295, rs4242382, rs6983267, rs7017300, rs7837688) and 17q12 (rs3760511, rs7501939) with PCa risk and progression. 150 patients with PCa, 150 patients with benign prostatic hyperplasia (BPH), and 100 men without clinical signs of prostate diseases (control group) were recruited as study participants. The genotyping was performed by using PCR-RFLP analysis and bidirectional DNA sequencing. Our study has shown association for all five analized variants in the region 8q24 (rs1447295, rs4242382, rs6983267, rs7017300 and rs7837688) and rs7501939 in the 17q12 region with the risk of PCa. Among 13 variants analyzed in our study, two (rs3760511 at 17q12 and rs1799983 at 7q36) have shown evidence of association with standard prognostic parameters of PCa. Our study yielded evidence of association of rs3760511 (17q12) and rs3198266 (7q36) with the risk of PCa progression. The results of our study have shown the scientific racionale for conducting casecontrol studies in Serbian population. The primal contribution of continuing reasearch regarding association between genetic variants and PCa risk and progression is in defining the minimal panel of single nuclotide variants which would be used as nonstandard prognostic parameters in PCa diagnostics and outcome prediction.