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Povezanost polimorfizama gena za glutation transferaze A1, M1, P1 i T1 sa rizikom za nastanak i progresijom karcinoma bubrežnog parenhima

dc.contributor.advisorPlješa-Ercegovac, Marija
dc.contributor.otherDžamić, Zoran
dc.contributor.otherSimić, Tatjana
dc.contributor.otherPekmezović, Tatjana
dc.contributor.otherSchmidinger, Manuela
dc.creatorĆorić, Vesna M.
dc.date.accessioned2017-06-13T14:04:59Z
dc.date.available2017-06-13T14:04:59Z
dc.date.available2020-07-03T08:52:39Z
dc.date.issued2017-04-13
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/8292
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=5035
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:15736/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=48964623
dc.description.abstractBackground: Cytosolic glutathione S-transferases (GSTs) might affect both the development and the progression of renal cell carcinoma (RCC) due to their dual functionality. The aim of this study was to evaluate specific role of GST gene variants (GSTA1, GSTM1, GSTT1 and GSTP1) as determinants of risk in patients with renal cell carcinoma, independently or simultaneously with recognized RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. Furthermore, we evaluated the effect of GST gene variants on postoperative prognosis in RCC patients. Special attention was paid to the most frequent type of RCC, clear renal cell carcinoma (ccRCC). Methods: GST genotypes were determined in 305 RCC patients and 326 matched-controls in whom overall survival was evaluated as well. The levels of benzo(a)pyrene diolepoxide (BPDE)-DNA adducts and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were determined by ELISA method. The expression of GSTM1 and GSTP1 protein level, as well as the level of regulatory (ASK1, JNK1/2) and executor (Caspase-3) apoptotic molecules in ccRCC tissue samples were analyzed by method of immuniblot. The presence of GSTM1:ASK1/ GSTP1:JNK1/2 protein:protein interactions was determined by means of immunoprecipitation. Results: Significant association between GST genotype and risk of overall RCC and ccRCC development was found for GSTM1-null and GSTP1-variant genotypes, independently (p<0.05). Furthermore, 22% of all recruited ccRCC patients were carriers of combined GSTM1-null/GSTT1-active/GSTA1-low activity/GSTP1-variant genotype, exhibiting 9.32-fold elevated ccRCC risk compared to the reference genotype combination (p=0.041). Significant association between GST genotype and ccRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with ccRCC, increasing the risk of ccRCC up to 7.57 (p=0.026)...en
dc.description.abstractUvod: Zbog uloga koje poseduju, citosolne glutation S-transferaze (GST) mogu biti značajne kako u nastanku, tako i u progresiji karcinoma bubrežnog parenhima (KBP). U ovoj studiji je ispitivana uloga pojedinih GST genskih varijanti (GSTA1, GSTM1, GSTT1 i GSTP1) u nastanku KBP, nezavisno ili udruženo sa poznatim faktorima rizika za nastanak ovog karcinoma, kao i moguća povezanost fenotipskih karakteristika tumora sa odgovarajućim genotipom. Pored toga, ispitivan je i potencijalni prognostički značaj polimorfne ekspresije GST proteina kod bolesnika sa KBP. Posebna pažnja je posvećena najučestalijem podtipu KBP, svetloćelijskom karcinomu bubrežnog parenhima (sKBP). Materijal i Metode: Polimorfizam GSTa je određivan kod 305 pacijenata sa KBP i kod 326 kontrola, uparenih po godinama i polu. Pored fenotipskih karakteristika tumora, u grupi pacijenata sa KPB je praćeno i preživljavanje. Nivoi benzo(a)piren diolepoksid (BPDE)-DNK-konjugata, kao i nivoi 8-hidroksi-2-deoksiguanozina (8-OHdG) su određivani ELISA metodom. Ekspresija GSTM1 i GSTP1 proteina, kao i ekspresija regulatornih (ASK1, JNK1/2) i egzekutornih (Caspaza 3) apoptotskih molekula u uzorcima tumorskog tkiva je analizirana metodom imunoblota. Prisustvo GSTM1:ASK1, odnosno GSTP1:JNK1/2 protein:proteinske interakcije je ispitivano metodom imunoprecipitacije. Rezultati: Uočen je značajan efekat GSTM1-nultog i GSTP1-varijantnog genotipa na rizik za nastanak KBP (p<0.05). Pored toga, 22% svih pacijenata sa sKBP su bili nosioci kombinovanog GSTM1-nultog/GSTT1-aktivnog/GSTA1-genotipa smanjene aktivnosti/GSTP1-varijantnog genotipa i bili su u 9.32 - puta većem riziku za nastanak sKBP u poređenju sa nosiocima referentnog genotipa (GSTM1-aktivni/GSTT1-nulti/GSTA1-aktivni/GSTP1-referentni genotip) (p=0.041). Uočen je efekat GSTP1-varijantnog genotipa na rizik za nastanak KBP kod pušača, dok je kombinacija GSTM1-nulti/GSTP1-varijantni/GSTA1-genotip smanjene aktivnosti bila prisutna u 94% pušača sa sKBP, povećavajući rizik od nastanka sKBP na 7.57 puta (p=0.026)...sr
dc.formatapplication/pdf
dc.languageen
dc.publisherУниверзитет у Београду, Медицински факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175052/RS//
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectGSTsr
dc.subjectGSTen
dc.subjectKBPen
dc.subjectriziken
dc.subjectprognozaen
dc.subjectpreživljavanjeen
dc.subjectBPDEen
dc.subject8-OHdGen
dc.subjectMAPKen
dc.subjectekspresija proteinaen
dc.subjectRCCsr
dc.subjectrisksr
dc.subjectprognosissr
dc.subjectsurvivalsr
dc.subjectBPDEsr
dc.subject8-OHdGsr
dc.subjectMAPKsr
dc.subjectprotein expressionsr
dc.titleThe association og glutathione transferase A1, M1 and T1 gene polymorphisms with the risk of renal cell carcinoma development and progressionen
dc.title.alternativePovezanost polimorfizama gena za glutation transferaze A1, M1, P1 i T1 sa rizikom za nastanak i progresijom karcinoma bubrežnog parenhimasr
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dcterms.abstractПљеша-Ерцеговац, Марија; Джамић, Зоран; Симић, Татјана; Пекмезовић, Татјана; Сцхмидингер, Мануела; Ћорић, Весна М.;
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/10666/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/10667/IzvestajKomisije10953.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/10667/IzvestajKomisije10953.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/10666/Disertacija.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_8292


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