Milošević, Goran

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  • Milošević, Goran (4)
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NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia

Ristivojević, Bojan; Kotur, Nikola; Tošić, Nataša; Stanković, Biljana; Gašić, Vladimir; Pavlović, Đorđe; Jelovac, Marina; Milošević, Goran; Pavlović, Sonja; Zukić, Branka

(Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade, 2023)

TY  - CONF
AU  - Ristivojević, Bojan
AU  - Kotur, Nikola
AU  - Tošić, Nataša
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Pavlović, Đorđe
AU  - Jelovac, Marina
AU  - Milošević, Goran
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2128
AB  - Introduction: The NUDT15 is new pharmacogene of importance for 6-mercaptopurine therapy, given to
children with acute lymphoblastic leukemia (ALL). The association ofside effectsin children with variants
in NUDT15 are well established in Asian populations, yet the relevance ofthis pharmacogene in European
populationsremainslargely unexplored. The aim of thisstudy wasto identify pharmacogenetic variants
in coding and neighbouring regions of NUDT15 gene and analyse if the expression levels of NUDT15 can
predict the occurence of side effects of 6-mercaptopurine during the maintenance therapy in children
with ALL of Serbian origin.
Methods: The genotyping of coding and neighbouring regions of NUDT15 gene was performed using
PCR and Sangersequencing based technology in 48 children with ALL. NUDT15 expression was analyzed
in mononuclear cells of 24 ALL patients at diagnosis and 6 healthy controls by qRT-PCR, and association
with surogate markers was assessed using adequate statistical methodology.
Results: The genotypig revealed the presence of 5 variantsin NUDT15 (NUDT15(NM_018283.4):c.36A>C,
NUDT15(NM_018283.4):c.158+117C>T,NUDT15(NM_018283.4):c.158+174G>A,NUDT15(NM_018283.4):c.159-
91G>A,NUDT15(NM_018283.4):c.*7G>A), none of them with effects on the expression or the function of
NUDT15 protein. There was no statistically significant association between the expression of NUDT15 at
diagnosis and the surogate markers of side effects (number of episodes of leukopenia (p=0.821), number of weeks without therapy (p=0.507), number of weeks with lower dose (p=0.434), average doses
(p=0.374)) of 6-mercaptopurine during the maintenance therapy.
Conclusion: Presently, NUDT15 cannot be used as a pharmacogene in predicting the toxicity of 6-mercaptopurine terapy in children with ALL in Serbia.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia
EP  - 81
SP  - 81
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2128
ER  - 
@conference{
author = "Ristivojević, Bojan and Kotur, Nikola and Tošić, Nataša and Stanković, Biljana and Gašić, Vladimir and Pavlović, Đorđe and Jelovac, Marina and Milošević, Goran and Pavlović, Sonja and Zukić, Branka",
year = "2023",
abstract = "Introduction: The NUDT15 is new pharmacogene of importance for 6-mercaptopurine therapy, given to
children with acute lymphoblastic leukemia (ALL). The association ofside effectsin children with variants
in NUDT15 are well established in Asian populations, yet the relevance ofthis pharmacogene in European
populationsremainslargely unexplored. The aim of thisstudy wasto identify pharmacogenetic variants
in coding and neighbouring regions of NUDT15 gene and analyse if the expression levels of NUDT15 can
predict the occurence of side effects of 6-mercaptopurine during the maintenance therapy in children
with ALL of Serbian origin.
Methods: The genotyping of coding and neighbouring regions of NUDT15 gene was performed using
PCR and Sangersequencing based technology in 48 children with ALL. NUDT15 expression was analyzed
in mononuclear cells of 24 ALL patients at diagnosis and 6 healthy controls by qRT-PCR, and association
with surogate markers was assessed using adequate statistical methodology.
Results: The genotypig revealed the presence of 5 variantsin NUDT15 (NUDT15(NM_018283.4):c.36A>C,
NUDT15(NM_018283.4):c.158+117C>T,NUDT15(NM_018283.4):c.158+174G>A,NUDT15(NM_018283.4):c.159-
91G>A,NUDT15(NM_018283.4):c.*7G>A), none of them with effects on the expression or the function of
NUDT15 protein. There was no statistically significant association between the expression of NUDT15 at
diagnosis and the surogate markers of side effects (number of episodes of leukopenia (p=0.821), number of weeks without therapy (p=0.507), number of weeks with lower dose (p=0.434), average doses
(p=0.374)) of 6-mercaptopurine during the maintenance therapy.
Conclusion: Presently, NUDT15 cannot be used as a pharmacogene in predicting the toxicity of 6-mercaptopurine terapy in children with ALL in Serbia.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia",
pages = "81-81",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2128"
}
Ristivojević, B., Kotur, N., Tošić, N., Stanković, B., Gašić, V., Pavlović, Đ., Jelovac, M., Milošević, G., Pavlović, S.,& Zukić, B.. (2023). NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 81-81.
https://hdl.handle.net/21.15107/rcub_imagine_2128
Ristivojević B, Kotur N, Tošić N, Stanković B, Gašić V, Pavlović Đ, Jelovac M, Milošević G, Pavlović S, Zukić B. NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:81-81.
https://hdl.handle.net/21.15107/rcub_imagine_2128 .
Ristivojević, Bojan, Kotur, Nikola, Tošić, Nataša, Stanković, Biljana, Gašić, Vladimir, Pavlović, Đorđe, Jelovac, Marina, Milošević, Goran, Pavlović, Sonja, Zukić, Branka, "NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):81-81,
https://hdl.handle.net/21.15107/rcub_imagine_2128 .

Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije

Gašić, Vladimir; Stanković, Biljana; Zukić, Branka; Janić, Dragana; Dokmanović, Lidija; Krstovski, Nada; Lazić, Jelena; Milošević, Goran; Lucafò, Marianna; Stocco, Gabriele; Decorti, Giuliana; Pavlović, Sonja; Kotur, Nikola

(Društvo medicinskih biohemičara Srbije, Beograd i Versita, 2019)

TY  - JOUR
AU  - Gašić, Vladimir
AU  - Stanković, Biljana
AU  - Zukić, Branka
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Milošević, Goran
AU  - Lucafò, Marianna
AU  - Stocco, Gabriele
AU  - Decorti, Giuliana
AU  - Pavlović, Sonja
AU  - Kotur, Nikola
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1269
AB  - Uvod: Ekspresija duge nekodirajuće RNK G AS5 je izme - njena u mnogim kancerima zbog njene uloge u apoptozi i inhibiciji rasta ćelije. G AS5 interaguje sa glukokortikoidnim receptorom, što je čini potencijalnim farmakotranskripcionim markerom značajnim za glukokortikoidnu terapiju. Naš cilj u ovoj studiji je bio da analiziramo ekspresiju GAS5 tokom indukcione terapije kod dečje akutne limfoblastne leukemije (ALL), u kojoj se koriste glukokortikoidni lekovi, i da te rezultate povežemo sa odgovorom na terapiju. Metode: Nivo ekspresije G AS5 u mononuklearnim ćelijama periferne krvi izolovanih od 29 dece obolelih od ALL, određen je metodologijom RT-qPCR, i to u momentu dijagnoze, 15. i 33. dana indukcione terapije. Rezultati: Naši rezultati su pokazali da postoje interindivi - dualne razlike u ekspresiji GAS5 kod pacijenata, i to u svim analiziranim tačkama. Kod svakog ALL pacijenta GAS5 ekspresija je 15. dana bila visa u odnosu na ekspresiju u momentu dijagnoze (p  lt  0,0005). Nivo ekspresije GAS5 je 33. dana bio niži u poređenju sa 15. danom (p  lt  0,0005), ali je i dalje bio značajno visi u odnosu na momenat dijagnoze kod većine pacijenata (p = 0,001). Pacijenti čiji je broj blasta u perifernoj krvi 8. dana bio ispod 100 po mikrolitru periferne krvi, imali su viši nivo ekspresije GAS5 (p = 0,016) i niži odnos ekspresija merenih 15. dana i u momentu dijagnoze (p = 0,009). Zaključak: Nasi rezultati ukazuju da bi nivo ekspresije GAS5 mogao da bude marker terapijskog odgovora u indukcionoj terapiji kod dece obolele od ALL.
AB  - Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing G AS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: G AS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in G AS5 expression at all time points. For each ALL patient, G A S5 expression was higher on day 15 in comparison to its level at diagnosis (p lt 0.0005). On day 33, the level of G A S5 expression decreased in comparison with day 15 (p lt 0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije
T1  - Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia
EP  - 298
IS  - 3
SP  - 292
VL  - 38
DO  - 10.2478/jomb-2018-0038
ER  - 
@article{
author = "Gašić, Vladimir and Stanković, Biljana and Zukić, Branka and Janić, Dragana and Dokmanović, Lidija and Krstovski, Nada and Lazić, Jelena and Milošević, Goran and Lucafò, Marianna and Stocco, Gabriele and Decorti, Giuliana and Pavlović, Sonja and Kotur, Nikola",
year = "2019",
abstract = "Uvod: Ekspresija duge nekodirajuće RNK G AS5 je izme - njena u mnogim kancerima zbog njene uloge u apoptozi i inhibiciji rasta ćelije. G AS5 interaguje sa glukokortikoidnim receptorom, što je čini potencijalnim farmakotranskripcionim markerom značajnim za glukokortikoidnu terapiju. Naš cilj u ovoj studiji je bio da analiziramo ekspresiju GAS5 tokom indukcione terapije kod dečje akutne limfoblastne leukemije (ALL), u kojoj se koriste glukokortikoidni lekovi, i da te rezultate povežemo sa odgovorom na terapiju. Metode: Nivo ekspresije G AS5 u mononuklearnim ćelijama periferne krvi izolovanih od 29 dece obolelih od ALL, određen je metodologijom RT-qPCR, i to u momentu dijagnoze, 15. i 33. dana indukcione terapije. Rezultati: Naši rezultati su pokazali da postoje interindivi - dualne razlike u ekspresiji GAS5 kod pacijenata, i to u svim analiziranim tačkama. Kod svakog ALL pacijenta GAS5 ekspresija je 15. dana bila visa u odnosu na ekspresiju u momentu dijagnoze (p  lt  0,0005). Nivo ekspresije GAS5 je 33. dana bio niži u poređenju sa 15. danom (p  lt  0,0005), ali je i dalje bio značajno visi u odnosu na momenat dijagnoze kod većine pacijenata (p = 0,001). Pacijenti čiji je broj blasta u perifernoj krvi 8. dana bio ispod 100 po mikrolitru periferne krvi, imali su viši nivo ekspresije GAS5 (p = 0,016) i niži odnos ekspresija merenih 15. dana i u momentu dijagnoze (p = 0,009). Zaključak: Nasi rezultati ukazuju da bi nivo ekspresije GAS5 mogao da bude marker terapijskog odgovora u indukcionoj terapiji kod dece obolele od ALL., Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing G AS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: G AS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in G AS5 expression at all time points. For each ALL patient, G A S5 expression was higher on day 15 in comparison to its level at diagnosis (p lt 0.0005). On day 33, the level of G A S5 expression decreased in comparison with day 15 (p lt 0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije, Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia",
pages = "298-292",
number = "3",
volume = "38",
doi = "10.2478/jomb-2018-0038"
}
Gašić, V., Stanković, B., Zukić, B., Janić, D., Dokmanović, L., Krstovski, N., Lazić, J., Milošević, G., Lucafò, M., Stocco, G., Decorti, G., Pavlović, S.,& Kotur, N.. (2019). Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 38(3), 292-298.
https://doi.org/10.2478/jomb-2018-0038
Gašić V, Stanković B, Zukić B, Janić D, Dokmanović L, Krstovski N, Lazić J, Milošević G, Lucafò M, Stocco G, Decorti G, Pavlović S, Kotur N. Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2019;38(3):292-298.
doi:10.2478/jomb-2018-0038 .
Gašić, Vladimir, Stanković, Biljana, Zukić, Branka, Janić, Dragana, Dokmanović, Lidija, Krstovski, Nada, Lazić, Jelena, Milošević, Goran, Lucafò, Marianna, Stocco, Gabriele, Decorti, Giuliana, Pavlović, Sonja, Kotur, Nikola, "Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 38, no. 3 (2019):292-298,
https://doi.org/10.2478/jomb-2018-0038 . .
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Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece

Dokmanović, Lidija; Milošević, Goran; Perić, Jelena; Tošić, Nataša; Krstovski, Nada; Janić, Dragana; Pavlović, Sonja

(Srpsko lekarsko društvo, Beograd, 2018)

TY  - JOUR
AU  - Dokmanović, Lidija
AU  - Milošević, Goran
AU  - Perić, Jelena
AU  - Tošić, Nataša
AU  - Krstovski, Nada
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1131
AB  - Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL.
AB  - Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece
T1  - Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia
EP  - 411
IS  - 7-8
SP  - 407
VL  - 146
DO  - 10.2298/SARH171003194D
ER  - 
@article{
author = "Dokmanović, Lidija and Milošević, Goran and Perić, Jelena and Tošić, Nataša and Krstovski, Nada and Janić, Dragana and Pavlović, Sonja",
year = "2018",
abstract = "Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL., Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece, Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia",
pages = "411-407",
number = "7-8",
volume = "146",
doi = "10.2298/SARH171003194D"
}
Dokmanović, L., Milošević, G., Perić, J., Tošić, N., Krstovski, N., Janić, D.,& Pavlović, S.. (2018). Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 146(7-8), 407-411.
https://doi.org/10.2298/SARH171003194D
Dokmanović L, Milošević G, Perić J, Tošić N, Krstovski N, Janić D, Pavlović S. Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece. in Srpski arhiv za celokupno lekarstvo. 2018;146(7-8):407-411.
doi:10.2298/SARH171003194D .
Dokmanović, Lidija, Milošević, Goran, Perić, Jelena, Tošić, Nataša, Krstovski, Nada, Janić, Dragana, Pavlović, Sonja, "Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece" in Srpski arhiv za celokupno lekarstvo, 146, no. 7-8 (2018):407-411,
https://doi.org/10.2298/SARH171003194D . .
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Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije

Milošević, Goran; Kotur, Nikola; Krstovski, Nada; Lazić, Jelena; Zukić, Branka; Stanković, Biljana; Janić, Dragana; Katsila, Theodora; Patrinos, George P.; Pavlović, Sonja; Dokmanović, Lidija

(Društvo medicinskih biohemičara Srbije, Beograd i Versita, 2018)

TY  - JOUR
AU  - Milošević, Goran
AU  - Kotur, Nikola
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Zukić, Branka
AU  - Stanković, Biljana
AU  - Janić, Dragana
AU  - Katsila, Theodora
AU  - Patrinos, George P.
AU  - Pavlović, Sonja
AU  - Dokmanović, Lidija
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1116
AB  - Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije.
AB  - Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije
T1  - Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia
EP  - 327
IS  - 3
SP  - 320
VL  - 37
DO  - 10.1515/jomb-2017-0060
ER  - 
@article{
author = "Milošević, Goran and Kotur, Nikola and Krstovski, Nada and Lazić, Jelena and Zukić, Branka and Stanković, Biljana and Janić, Dragana and Katsila, Theodora and Patrinos, George P. and Pavlović, Sonja and Dokmanović, Lidija",
year = "2018",
abstract = "Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije., Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije, Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia",
pages = "327-320",
number = "3",
volume = "37",
doi = "10.1515/jomb-2017-0060"
}
Milošević, G., Kotur, N., Krstovski, N., Lazić, J., Zukić, B., Stanković, B., Janić, D., Katsila, T., Patrinos, G. P., Pavlović, S.,& Dokmanović, L.. (2018). Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 37(3), 320-327.
https://doi.org/10.1515/jomb-2017-0060
Milošević G, Kotur N, Krstovski N, Lazić J, Zukić B, Stanković B, Janić D, Katsila T, Patrinos GP, Pavlović S, Dokmanović L. Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2018;37(3):320-327.
doi:10.1515/jomb-2017-0060 .
Milošević, Goran, Kotur, Nikola, Krstovski, Nada, Lazić, Jelena, Zukić, Branka, Stanković, Biljana, Janić, Dragana, Katsila, Theodora, Patrinos, George P., Pavlović, Sonja, Dokmanović, Lidija, "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 37, no. 3 (2018):320-327,
https://doi.org/10.1515/jomb-2017-0060 . .
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