The analysis of redox homeostasis genetic biomarkers as risk factors for clear cell renal cell carcinoma development and progression

[S. Mihailović]

95 str.

Medicina - Biologija tumora i oksidativna oboljenja / Medicine - Biology of tumors and oxidative diseases

Uvod: Hemijske reakcije koje se kontinuirano odvijaju na ćelijskom nivou, praćene su nepotpunom redukcijom kiseonika čime nastaju kiseonični slobodni radikali (engl. reactive oxygen species, ROS). Njihovo prisustvo aktivira niz antioksidantnih sistema koji će raditi na uklanjanju ROS. Aktivacija nuklearnog faktora povezanog sa eritroid 2-faktorom 2 (engl. nuclear factor erythroid 2-related factor 2, Nrf2), dovodi do ekspresije enzima, poput superoksid dizmutaza (SOD), glutation peroksidaza (GPX) i glutation S-transferaza (GST), koji učestvuju u antioksidantnom odgovoru. Tumorska mikrosredina sa prooksidantnom aktivnošću ima veliki značaj u nastanku i daljoj progresiji svetloćelijskog karcinoma bubrežnog parenhima. Cilj ovog ispitivanja bio je da se ispita da li najčešći genetski polimorfizmi za gene Nrf2, SOD2, GPX1 i GSTP1 mogu imati uticaj na nastanak sKBP. Materijal i metode: Sprovedena je genotipizacija polimorfizama Nrf2 (rs6721961), SOD2 (rs4880), GPX1 (rs1050450) kao i GSTP1 (rs1695, rs1138272) kod 223 pacijenta sa dijagnozom sKBP i 336 pripadnika kontrolne grupe, odgovarajućim metodama reakcije lančanog umnožavanja (engl. PCR). Ispitivana je povezanost pomenutih polimorfizama sa rizikom za nastanak sKBP, kao i sa fenotipskim karakteristikama tumora i postojanje udruženog efekta sa poznatim faktorima rizika za nastanak KBP. Takođe je praćeno preživljavanje pacijenata nakon učinjene hirurške resekcije tumora u periodu od 13 godina, i mogući prognostički značaj ispitivanih polimorfizama. Rezultati: Osobe nosioci varijantnih genotipova za SOD2 polimorfizam imaju 4,5 puta veći rizik za nastanak sKBP u odnosu na nosioce referentnog genotipa (p<0,001). Osobe nosioci varijantnih genotipova za GSTP1 rs1695 polimorfizam, koje su istovremeno nosioci referentnog genotipa za rs1138272, imaju 3,2 puta veći rizik za nastanak sKBP (p=0,001), dok je ispitivanjem haplotipa za navedene polimorfizme pokazano da su u 3,5 puta većem riziku osobe nosioci Val105 i Val114 genotipa u odnosu na nosioce referentne kombinacije Ile105 i Ala114 (p=0,004). Hipertenzivni ispitanici, koji su uz to nosioci varijantnih genotipova za SOD2, imaju čak 12 puta veći rizik za nastanak sKBP u odnosu na referentnu grupu (p<0,001). Ispitivani polimorfizmi nisu predstavljali značajan prognostički faktor među pacijentima obolelim od sKBP. Međutim, nosioci varijantnih kombinacija ispitivanih GSTP1 rs1695 i rs1138272 polimorfizama imali su kraći period preživljavanja nakon nerfrektomije. Zaključak: Pojedini polimorfizmi gena koji kodiraju antiokioksidantne enzime mogu biti povezani sa nastankom sKBP, posebno varijantni genotipovi SOD2 rs4880 i varijantni genotipovi GSTP1 rs1695 i rs1138272 polimorfizama. Rizik za nastanak sKBP se dodatno povećava kada su ovi rizični genotipovi prisutni u kombinaciji. Takođe, nosioci kombinovanih varijantnih genotipova rs1695 i rs1138272 GSTP1, imali su kraći period preživljavanja u odnosu na nosioce kombinacije referentnih genotipova.

Introduction: Continuous cellular chemical reactions result in incomplete oxygen reaction which produce reactive oxygen species (ROS). Their accumultation stimulates activation of antioxidative systems as resistance mechanisms. Activated nuclear factor erythroid 2-related factor 2 (Nrf2) further causes antioxidant enzymes expression, such as superoxide dismutases (SOD), glutathione peroxidases (GPX), as well as glutathione S-transferases (GST). Prooxidant tumor environment is of great significance for promoting development and progression of clear cell renal cell carcinoma (ccRCC). The aim of this study was to evaluate importance of genetic polymorphisms of Nrf2, GSTP1, SOD2 and GPX1 genes in case of ccRCC. Material and methods: Genotyping of Nrf2 (rs6721961), SOD2 (rs4880), GPX1 (rs1050450) and GSTP1 (rs1695, rs1138272) polymorphisms was performed in 223 cases of ccRCC and 336 matched controls by polymerase chain reaction. The connection between investigated polmorphysms and risk for ccRCC development, as well as their relation to tumor fenotype characteristics with or without contributing factors, were examined. Furthermore, overall survival after surgical resection in relation to beformentioned genotypes, was studied during the course of 13 years. Results: Carriers of SOD2 variant genotypes expressed 4.5 fold increased risk for ccRCC in comparison to referent genotype carriers (p<0.001). Similarly, variant genotypes carriers of GSTP1 rs1695 also carrying referent rs1138272 genotype, exhibited 3.2 fold increased risk (p=0.001), while haplotype analysis for two GSTP1 polymorphisms showed 3.5 fold increased risk for Val105 and Val114 carriers in comparison to referent combination consisting of Ile105 and Ala114 (p=0.004). Hypertension as risk factor in combination with variant SOD2 genotype had 12 fold increased risk for ccRCC compared to referent group (p<0.001). Examined polymorphisms were not shown to be of significant prognostic importance for patients with ccRCC, although variant genotype carriers of examined GSTP1 polymorphisms did have shorter overall survival. Conclusions: Certain gene polymorphisms encoding antioxidant enzymes might be associated with the risk for ccRCC, with emphasis on variant genotype of SOD2 rs4880 polymorphism and variant genotypes of rs1695 and rs1138272 GSTP1 polymorphisms. Combination of these genotypes may even further significantly increase the risk. Furthermore, carriers of variant genotypes of rs1695 and rs1138272 GSTP1 polymorphisms had shorter survival period in comparison to individuals with referent combination of these genotypes.

svetloćelijski karcinom bubrežnog parenhima, Nrf2, GSTP1, SOD2, GPX1, redoks homeostaza

clear cell renal cell carcinoma, Nrf2, GSTP1, SOD2, GPX1, redox homeostasis

616.61-006.6:577.2(043.3)

Tekst