Title
The association of glutathione transferase A1, M1, P1 and T1 gene polymorphisms with the risk of renal cell carcinoma development and progression
Creator
Ćorić, Vesna M., 1985-
Copyright date
2017
Object Links
Select license
Autorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
License description
Dozvoljavate samo preuzimanje i distribuciju dela, ako/dok se pravilno naznačava ime autora, bez ikakvih promena dela i bez prava komercijalnog korišćenja dela. Ova licenca je najstroža CC licenca. Osnovni opis Licence: http://creativecommons.org/licenses/by-nc-nd/3.0/rs/deed.sr_LATN. Sadržaj ugovora u celini: http://creativecommons.org/licenses/by-nc-nd/3.0/rs/legalcode.sr-Latn
Language
English
Cobiss-ID
Committee report
Theses Type
Doktorska disertacija
description
Datum odbrane: 13.04.2017.
Other responsibilities
mentor
Plješa-Ercegovac, Marija, 1976-
komentor
Džamić, Zoran, 1960-
član komisije
Simić, Tatjana, 1964-
član komisije
Pekmezović, Tatjana, 1964-
član komisije
Schmidinger, Manuela
Academic Expertise
Medicinske nauke
University
Univerzitet u Beogradu
Faculty
Medicinski fakultet
Alternative title
Povezanost polimorfizama gena za glutation transferaze A1, M1, P1 i T1 sa rizikom za nastanak i progresijom karcinoma bubrežnog parenhima
Publisher
[ V. Ćorić]
Format
119 listova
description
Medicine - Medical and clinical biochemistry / Medicina
- Medicinska i klinička biohemija
Abstract (en)
Background: 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)...
Abstract (sr)
Uvod: 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)...
Authors Key words
GST, RCC, risk, prognosis, survival, BPDE, 8-OHdG, MAPK, protein expression
Authors Key words
GST, KBP, rizik, prognoza, preživljavanje, BPDE, 8-OHdG, MAPK, ekspresija proteina
Classification
616.61-006.6:577.15(043.3)
Type
Tekst
Abstract (en)
Background: 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)...
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