TY  - JOUR
AU  - Nedeljković, Milica
AU  - Tanić, Nikola
AU  - Dramićanin, Tatjana
AU  - Milovanović, Zorka
AU  - Šušnjar, Snežana
AU  - Milinković, Vedrana
AU  - Vujović, Ivana
AU  - Tanić, Nasta
PY  - 2018
UR  - http://content.sciendo.com/view/journals/jomb/ahead-of-print/article-10.1515-jomb-2018-0012.xml
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3062
AB  - Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.
T2  - Journal of Medical Biochemistry
T1  - Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer
DO  - 10.1515/jomb-2018-0012
ER  - 

@article{
author = "Nedeljković, Milica and Tanić, Nikola and Dramićanin, Tatjana and Milovanović, Zorka and Šušnjar, Snežana and Milinković, Vedrana and Vujović, Ivana and Tanić, Nasta",
year = "2018",
abstract = "Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.",
journal = "Journal of Medical Biochemistry",
title = "Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer",
doi = "10.1515/jomb-2018-0012"
}

Nedeljković, M., Tanić, N., Dramićanin, T., Milovanović, Z., Šušnjar, S., Milinković, V., Vujović, I.,& Tanić, N.. (2018). Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer. in Journal of Medical Biochemistry.
https://doi.org/10.1515/jomb-2018-0012

Nedeljković M, Tanić N, Dramićanin T, Milovanović Z, Šušnjar S, Milinković V, Vujović I, Tanić N. Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer. in Journal of Medical Biochemistry. 2018;.
doi:10.1515/jomb-2018-0012 .

Nedeljković, Milica, Tanić, Nikola, Dramićanin, Tatjana, Milovanović, Zorka, Šušnjar, Snežana, Milinković, Vedrana, Vujović, Ivana, Tanić, Nasta, "Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer" in Journal of Medical Biochemistry (2018),
https://doi.org/10.1515/jomb-2018-0012 . .

TY  - JOUR
AU  - Tanić, Nasta
AU  - Milinković, Vedrana
AU  - Dramićanin, Tatjana
AU  - Nedeljković, Milica
AU  - Stanković, Tijana
AU  - Milovanović, Zorka
AU  - Šušnjar, Snežana
AU  - Milošević, Verica
AU  - Šošić-Jurjević, Branka 
AU  - Džodić, Radan
AU  - Tanić, Nikola
PY  - 2013
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/502
AB  - Background: Breast cancer is the most common form of cancer in women. It arises from multiple genetic changes in oncogenes and tumor suppressor genes. Among so far studied oncogenes relatively few, including epdermal growth factor receptor (EGfR), cyclinD1 (CCNDİ)and c-myc, have been found to play an important role in progression of this type of human malignancy. The aim of this study was to examine the prognostic potential of CCND1, c-myc and EGFR amplification and their possible cooperation in breast carcinogenesis. Methods: Copy number analyses of CCND1 and c-myc genes were done by TaqMan based quantitative real time PCR. Amplification status of EGFR was determined by differential Pcr. Results: Amplification of CCND1, c-myc and EGFR oncogene has been found in 20.4%, 26.5% and 26.5% of breast cancer cases, respectively. Analysis showed that amplification of CCND1 oncogene was significantly associated with the stage II of disease while amplification of EGFR gene was significantly associated with overexpression of HER-2/neu. Tumour stage and expression of HER-2/neu appeared to be significant predictors of patient's outcome. Stage I patients lived significantly longer then stage III patients (p=0.04) while patients with HER-2/neu overexpression had worse prognoses and lived significantly shorter (p=0.001). Finally, survival of patients who underwent hormone therapy only was significantly longer (p=0.001) then survival of the rest of patients. Conclusions: Amplification of CCND1 or EGFR oncogene is associated with the progression of breast cancer and bad prognosis. No co-ordination in amplification of CCND1, c-myc and EGFR oncogenes were established in this cohort of breast cancer patients.
AB  - Uvod: Kancer dojke je najčešći tip maligniteta koji se javljaju kod žena. Tumori dojke nastaju kao rezultat akumulacije genetičkih promena kako u onkogenima tako i u tumor supresorskim genima. Među mnogim onkogenima čija je uloga u genezi tumora dojke ispitivana do danas, samo se neki smatraju značajnim za razviće ovih karcinoma. U tu se grupu svakako ubrajaju receptor za epidermalni factor rasta (EGFR), c-myc i ciklinD1 (CCND1). Cilj rada je bio utvrditi prognostički značaj amplifikacije CCND1, c-myc i EGFR onkogena u razviću tumora dojke kao i eventualne međusobne koalteracije ovih gena. Metode: Amplifikacioni status CCND1 i c-myc gena određen je kvantitativnim PCR-om u realnom vremenu, a amplifikacioni status EGFR onkogena je definisan diferencijalnim PCR-om. Rezultati: Amplifikacija CCND1 gena detektovana je kod 20.4%, a c-myc i EGFR onkogena kod 26.5% ispitanih uzoraka. Analize su pokazale da je amplifikacija CCND1 onkogena statistički značajno povezana sa stadijumom II tumora dojke kao i da amplifikacija EGFR-a značajno korelira sa povećanom ekspresijom HER2/neu. Analize kliničkih i histopatoloških parametara su jasno pokazale da stadijum tumora i nivo ekspresije HER2/neu gena predstavljaju značajne pokazatelje daljeg toka bolesti, odnosno sudbine pacijenta. Utvrđeno je da pacijentkinje sa tumorima dojke stadijuma I žive značajno duže od onih sa tumorom stadijuma III (p= 0.04) kao i da pacijentkinje sa HER2/neu pozitivnim statusom imaju goru prognozu i žive značajno krace (p=0.001). Na kraju, studija je pokazala da pacijentkinje podvrgnute samo hormonskoj terapiji imaju najbolju prognozu i žive značajno duže od ostalih (p=0.001). Zaključak: Amplifikacija CCND1 i EGFR onkogena je povezana sa lošom prognozom i progresijom karcinoma dojke. U ispitivanom tumorskom uzorku nisu detektovane nikakve koalteracije CCND1, c-myc i EGFR onkogena.
T2  - Journal of Medical Biochemistry
T1  - Amplifikacija ciklin D1, c-myc i EGFR onkogena u tumorskim uzorcima pacijentkinja obolelih od kancera dojke
T1  - Amplification of cycline D1, c-myc and EGFR oncogenes in tumour samples of breast cancer patients
IS  - 4
VL  - 32
DO  - 10.2478/jomb-2014-0005
SP  - 339
EP  - 346
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_502
ER  - 

@article{
author = "Tanić, Nasta and Milinković, Vedrana and Dramićanin, Tatjana and Nedeljković, Milica and Stanković, Tijana and Milovanović, Zorka and Šušnjar, Snežana and Milošević, Verica and Šošić-Jurjević, Branka  and Džodić, Radan and Tanić, Nikola",
year = "2013",
abstract = "Background: Breast cancer is the most common form of cancer in women. It arises from multiple genetic changes in oncogenes and tumor suppressor genes. Among so far studied oncogenes relatively few, including epdermal growth factor receptor (EGfR), cyclinD1 (CCNDİ)and c-myc, have been found to play an important role in progression of this type of human malignancy. The aim of this study was to examine the prognostic potential of CCND1, c-myc and EGFR amplification and their possible cooperation in breast carcinogenesis. Methods: Copy number analyses of CCND1 and c-myc genes were done by TaqMan based quantitative real time PCR. Amplification status of EGFR was determined by differential Pcr. Results: Amplification of CCND1, c-myc and EGFR oncogene has been found in 20.4%, 26.5% and 26.5% of breast cancer cases, respectively. Analysis showed that amplification of CCND1 oncogene was significantly associated with the stage II of disease while amplification of EGFR gene was significantly associated with overexpression of HER-2/neu. Tumour stage and expression of HER-2/neu appeared to be significant predictors of patient's outcome. Stage I patients lived significantly longer then stage III patients (p=0.04) while patients with HER-2/neu overexpression had worse prognoses and lived significantly shorter (p=0.001). Finally, survival of patients who underwent hormone therapy only was significantly longer (p=0.001) then survival of the rest of patients. Conclusions: Amplification of CCND1 or EGFR oncogene is associated with the progression of breast cancer and bad prognosis. No co-ordination in amplification of CCND1, c-myc and EGFR oncogenes were established in this cohort of breast cancer patients., Uvod: Kancer dojke je najčešći tip maligniteta koji se javljaju kod žena. Tumori dojke nastaju kao rezultat akumulacije genetičkih promena kako u onkogenima tako i u tumor supresorskim genima. Među mnogim onkogenima čija je uloga u genezi tumora dojke ispitivana do danas, samo se neki smatraju značajnim za razviće ovih karcinoma. U tu se grupu svakako ubrajaju receptor za epidermalni factor rasta (EGFR), c-myc i ciklinD1 (CCND1). Cilj rada je bio utvrditi prognostički značaj amplifikacije CCND1, c-myc i EGFR onkogena u razviću tumora dojke kao i eventualne međusobne koalteracije ovih gena. Metode: Amplifikacioni status CCND1 i c-myc gena određen je kvantitativnim PCR-om u realnom vremenu, a amplifikacioni status EGFR onkogena je definisan diferencijalnim PCR-om. Rezultati: Amplifikacija CCND1 gena detektovana je kod 20.4%, a c-myc i EGFR onkogena kod 26.5% ispitanih uzoraka. Analize su pokazale da je amplifikacija CCND1 onkogena statistički značajno povezana sa stadijumom II tumora dojke kao i da amplifikacija EGFR-a značajno korelira sa povećanom ekspresijom HER2/neu. Analize kliničkih i histopatoloških parametara su jasno pokazale da stadijum tumora i nivo ekspresije HER2/neu gena predstavljaju značajne pokazatelje daljeg toka bolesti, odnosno sudbine pacijenta. Utvrđeno je da pacijentkinje sa tumorima dojke stadijuma I žive značajno duže od onih sa tumorom stadijuma III (p= 0.04) kao i da pacijentkinje sa HER2/neu pozitivnim statusom imaju goru prognozu i žive značajno krace (p=0.001). Na kraju, studija je pokazala da pacijentkinje podvrgnute samo hormonskoj terapiji imaju najbolju prognozu i žive značajno duže od ostalih (p=0.001). Zaključak: Amplifikacija CCND1 i EGFR onkogena je povezana sa lošom prognozom i progresijom karcinoma dojke. U ispitivanom tumorskom uzorku nisu detektovane nikakve koalteracije CCND1, c-myc i EGFR onkogena.",
journal = "Journal of Medical Biochemistry",
title = "Amplifikacija ciklin D1, c-myc i EGFR onkogena u tumorskim uzorcima pacijentkinja obolelih od kancera dojke, Amplification of cycline D1, c-myc and EGFR oncogenes in tumour samples of breast cancer patients",
number = "4",
volume = "32",
doi = "10.2478/jomb-2014-0005",
pages = "339-346",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_502"
}

Tanić, N., Milinković, V., Dramićanin, T., Nedeljković, M., Stanković, T., Milovanović, Z., Šušnjar, S., Milošević, V., Šošić-Jurjević, B., Džodić, R.,& Tanić, N.. (2013). Amplifikacija ciklin D1, c-myc i EGFR onkogena u tumorskim uzorcima pacijentkinja obolelih od kancera dojke. in Journal of Medical Biochemistry, 32(4), 339-346.
https://doi.org/10.2478/jomb-2014-0005
https://hdl.handle.net/21.15107/rcub_ibiss_502

Tanić N, Milinković V, Dramićanin T, Nedeljković M, Stanković T, Milovanović Z, Šušnjar S, Milošević V, Šošić-Jurjević B, Džodić R, Tanić N. Amplifikacija ciklin D1, c-myc i EGFR onkogena u tumorskim uzorcima pacijentkinja obolelih od kancera dojke. in Journal of Medical Biochemistry. 2013;32(4):339-346.
doi:10.2478/jomb-2014-0005
https://hdl.handle.net/21.15107/rcub_ibiss_502 .

Tanić, Nasta, Milinković, Vedrana, Dramićanin, Tatjana, Nedeljković, Milica, Stanković, Tijana, Milovanović, Zorka, Šušnjar, Snežana, Milošević, Verica, Šošić-Jurjević, Branka , Džodić, Radan, Tanić, Nikola, "Amplifikacija ciklin D1, c-myc i EGFR onkogena u tumorskim uzorcima pacijentkinja obolelih od kancera dojke" in Journal of Medical Biochemistry, 32, no. 4 (2013):339-346,
https://doi.org/10.2478/jomb-2014-0005 .,
https://hdl.handle.net/21.15107/rcub_ibiss_502 .

TY  - THES
AU  - Milinković, Vedrana
PY  - 2013
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=1087
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:7792/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1024573874
UR  - http://nardus.mpn.gov.rs/123456789/2160
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2396
AB  - Glioblastomi (GBM) predstavljaju najčešći i najmaligniji tip tumora mozga. Iako imaju istu
histopatološku sliku, primarni i sekundarni glioblastomi se razlikuju po mehanizmu nastanka
i setu karakterističnih genetičkih promena. Iako je tokom poslednjih godina došlo do
određenog poboljšanja u sagledavanju njihove kompleksne prirode, glioblastomi i dalje
predstavljaju neizlečivu bolest. Osnovni cilj ove doktorske disertacije bio je detekcija i
kvantifikacija genomske nestabilnosti, kao i identifikacija specifičnih genetičkih promena
odgovornih za promociju i progresiju malignih glioma, a sa dugoročnim ciljem da se definišu
potencijalni molekularni markeri za dijagnozu i prognozu bolesti. Sa tim u vezi, izvršena je i
analiza najčešćih poznatih genetičkih promena u gliomima: detekcija inaktivacije ključnih
tumor supresor gena (p53, PTEN i p16) i amplifikacije EGFR onkogena. Promene dva ili više
navedenih gena su prisutne u većini analiziranih uzoraka, što potvrđuje značaj višestrukih
genskih alteracija u patogenezi glioma.
Upoređivanjem AP-PCR DNK profila tumorskog i zdravog tkiva pacijenata uočena su dva
tipa razlika: kvalitativne razlike koje nastaju usled promena u sekvenci DNK molekula i
predstavljaju manifestaciju mikrosatelitske nestabilnosti i nestabilnosti pojedinačnih
nukleotida (MIN-PIN), kao i kvantitativne razlike nastale usled amplifikacija ili delecija
većih hromozomskih regiona, pokazatelj hromozomske nestabilnosti (CIN). Oba tipa
promena su prisutna u svim analiziranim uzorcima, doprinoseći podjednako visokom stepenu
ukupne genomske nestabilnosti u oba histološka podtipa GBM. Detaljnija analiza DNK
profila je omogućila identifikaciju specifičnih promena 11 novih gena, koji do sada nisu
povezani sa progresijom glioma: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2,
KCNG2, PDE4D, KIR3DL3 i INPP5A. Većina identifikovanih gena ima značajnu ulogu u
procesima signalne transdukcije i ćelijske adhezije, koji su veoma značajni za nastanak i
progresiju kancera. Prisustvo promena u identifikovanim genima je, dalje, korelisano sa
kliničko-patološkim parametrima, stepenom genomske nestabilnosti i preživljavanjem
pacijenata, kao i sa statusom p53, PTEN, p16 i EGFR gena. Pokazane su statistički značajne
ko-alteracije nekih od identifikovanih gena sa p53, p16 i EGFR genima, ali nije pokazana
statistički značajna povezanost između inaktiviranog PTEN-a i bilo kojeg novog
identifikovanog gena. Svi rezultati ove studije potvrđuju da se u osnovi glioma nalaze
izuzetno složeni genetički mehanizmi, pri čemu je naročito značajan visok stepen genomske
nestabilnosti koji potencijalno predstavlja jednu od osnovnih karakteristika ovog tipa
tumora. Osim toga, ova studiija je prva koja je ukazala na potencijalni značaj
identifikovanih gena u patogenezi glioma, kao i na njihovu primenu kao potencijalnih
biomarkera za dijagnostiku i prognozu pacijenata sa primarnim ili sekundarnim
glioblastomima.
AB  - Glioblastoma is the most frequent and the most malignant human brain tumor. Despite a similar
histological appearance, primary and secondary glioblastomas are distinct tumor entities with
different genetic alterations but none being specific enough to distinguish them. Despite better
insight in its complex genetic nature, glioblastoma is still incurable disease, with extremely
short median survival. The purpose of this study was to detect specific genetic changes, as well
as to quantify overall level of genomic instability in samples of malignant glioma patients.
Besides, we analyzed genetic alterations of key tumor suppressors (p53, PTEN and p16) and
EGFR oncogene, commonly aberrant in glioma samples. Alterations of two or more genes were
present in majority of analyzed samples indicating importance of multiple changes for
gliomagenesis.
AP-PCR DNA profiling revealed two types of genetic differences between tumor and normal
tissue: qualitative changes which represent accumulation of changes in DNA sequence and are
the manifestation of microsatellite and point mutation instability (MIN-PIN) and quantitative
changes which represent amplifications or deletions of existing chromosomal material and are
the manifestation of chromosomal instability (CIN). Both types of alterations were present in
all analyzed samples contributing almost equally to the total level of genomic instability, and
showing no differences between histological subtypes. Further investigation of alterations in
DNA profiles revealed specific changes in the following 11 genes that were not previously
associated with glioma pathogenesis: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2,
KCNG2, PDE4D, KIR3DL3, and INPP5A. Most of identified genes have significant role in
signal transduction or cell adhesion, which are important processes for cancer development and
progression.
The frequencies of observed alterations were correlated with clinicopathologic parameters, the
level of genomic instability and patient survival, as well as with presence of alterations in p53,
PTEN, p16 and EGFR genes. Some of the identified genes showed significant association with
p53 and p16 tumor suppressors, as well as with EGFR, but there was no significant correlation
between loss of PTEN and any of identified genes.
In conclusion, our results confirmed complexity of glioma genetic nature, emphasizing high
level of genomic instability as hallmark of this tumor type. Identified novel genes could be used
as potential biomarkers for diagnosis of primary and secondary glioblastoma, as well as
predictors of patients’ outcome.
PB  - Belgrade: University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Detekcija i karakterizacija genomske nestabilnosti tumora mozga glijalnog porekla
T1  - Detection and characterization of genomic instability in patients with malignant glioma
SP  - 1
EP  - 140
UR  - https://hdl.handle.net/21.15107/rcub_nardus_2160
ER  - 

@phdthesis{
author = "Milinković, Vedrana",
year = "2013",
abstract = "Glioblastomi (GBM) predstavljaju najčešći i najmaligniji tip tumora mozga. Iako imaju istu
histopatološku sliku, primarni i sekundarni glioblastomi se razlikuju po mehanizmu nastanka
i setu karakterističnih genetičkih promena. Iako je tokom poslednjih godina došlo do
određenog poboljšanja u sagledavanju njihove kompleksne prirode, glioblastomi i dalje
predstavljaju neizlečivu bolest. Osnovni cilj ove doktorske disertacije bio je detekcija i
kvantifikacija genomske nestabilnosti, kao i identifikacija specifičnih genetičkih promena
odgovornih za promociju i progresiju malignih glioma, a sa dugoročnim ciljem da se definišu
potencijalni molekularni markeri za dijagnozu i prognozu bolesti. Sa tim u vezi, izvršena je i
analiza najčešćih poznatih genetičkih promena u gliomima: detekcija inaktivacije ključnih
tumor supresor gena (p53, PTEN i p16) i amplifikacije EGFR onkogena. Promene dva ili više
navedenih gena su prisutne u većini analiziranih uzoraka, što potvrđuje značaj višestrukih
genskih alteracija u patogenezi glioma.
Upoređivanjem AP-PCR DNK profila tumorskog i zdravog tkiva pacijenata uočena su dva
tipa razlika: kvalitativne razlike koje nastaju usled promena u sekvenci DNK molekula i
predstavljaju manifestaciju mikrosatelitske nestabilnosti i nestabilnosti pojedinačnih
nukleotida (MIN-PIN), kao i kvantitativne razlike nastale usled amplifikacija ili delecija
većih hromozomskih regiona, pokazatelj hromozomske nestabilnosti (CIN). Oba tipa
promena su prisutna u svim analiziranim uzorcima, doprinoseći podjednako visokom stepenu
ukupne genomske nestabilnosti u oba histološka podtipa GBM. Detaljnija analiza DNK
profila je omogućila identifikaciju specifičnih promena 11 novih gena, koji do sada nisu
povezani sa progresijom glioma: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2,
KCNG2, PDE4D, KIR3DL3 i INPP5A. Većina identifikovanih gena ima značajnu ulogu u
procesima signalne transdukcije i ćelijske adhezije, koji su veoma značajni za nastanak i
progresiju kancera. Prisustvo promena u identifikovanim genima je, dalje, korelisano sa
kliničko-patološkim parametrima, stepenom genomske nestabilnosti i preživljavanjem
pacijenata, kao i sa statusom p53, PTEN, p16 i EGFR gena. Pokazane su statistički značajne
ko-alteracije nekih od identifikovanih gena sa p53, p16 i EGFR genima, ali nije pokazana
statistički značajna povezanost između inaktiviranog PTEN-a i bilo kojeg novog
identifikovanog gena. Svi rezultati ove studije potvrđuju da se u osnovi glioma nalaze
izuzetno složeni genetički mehanizmi, pri čemu je naročito značajan visok stepen genomske
nestabilnosti koji potencijalno predstavlja jednu od osnovnih karakteristika ovog tipa
tumora. Osim toga, ova studiija je prva koja je ukazala na potencijalni značaj
identifikovanih gena u patogenezi glioma, kao i na njihovu primenu kao potencijalnih
biomarkera za dijagnostiku i prognozu pacijenata sa primarnim ili sekundarnim
glioblastomima., Glioblastoma is the most frequent and the most malignant human brain tumor. Despite a similar
histological appearance, primary and secondary glioblastomas are distinct tumor entities with
different genetic alterations but none being specific enough to distinguish them. Despite better
insight in its complex genetic nature, glioblastoma is still incurable disease, with extremely
short median survival. The purpose of this study was to detect specific genetic changes, as well
as to quantify overall level of genomic instability in samples of malignant glioma patients.
Besides, we analyzed genetic alterations of key tumor suppressors (p53, PTEN and p16) and
EGFR oncogene, commonly aberrant in glioma samples. Alterations of two or more genes were
present in majority of analyzed samples indicating importance of multiple changes for
gliomagenesis.
AP-PCR DNA profiling revealed two types of genetic differences between tumor and normal
tissue: qualitative changes which represent accumulation of changes in DNA sequence and are
the manifestation of microsatellite and point mutation instability (MIN-PIN) and quantitative
changes which represent amplifications or deletions of existing chromosomal material and are
the manifestation of chromosomal instability (CIN). Both types of alterations were present in
all analyzed samples contributing almost equally to the total level of genomic instability, and
showing no differences between histological subtypes. Further investigation of alterations in
DNA profiles revealed specific changes in the following 11 genes that were not previously
associated with glioma pathogenesis: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2,
KCNG2, PDE4D, KIR3DL3, and INPP5A. Most of identified genes have significant role in
signal transduction or cell adhesion, which are important processes for cancer development and
progression.
The frequencies of observed alterations were correlated with clinicopathologic parameters, the
level of genomic instability and patient survival, as well as with presence of alterations in p53,
PTEN, p16 and EGFR genes. Some of the identified genes showed significant association with
p53 and p16 tumor suppressors, as well as with EGFR, but there was no significant correlation
between loss of PTEN and any of identified genes.
In conclusion, our results confirmed complexity of glioma genetic nature, emphasizing high
level of genomic instability as hallmark of this tumor type. Identified novel genes could be used
as potential biomarkers for diagnosis of primary and secondary glioblastoma, as well as
predictors of patients’ outcome.",
publisher = "Belgrade: University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Detekcija i karakterizacija genomske nestabilnosti tumora mozga glijalnog porekla, Detection and characterization of genomic instability in patients with malignant glioma",
pages = "1-140",
url = "https://hdl.handle.net/21.15107/rcub_nardus_2160"
}

Milinković, V.. (2013). Detekcija i karakterizacija genomske nestabilnosti tumora mozga glijalnog porekla. in University of Belgrade, Faculty of Biology
Belgrade: University of Belgrade, Faculty of Biology., 1-140.
https://hdl.handle.net/21.15107/rcub_nardus_2160

Milinković V. Detekcija i karakterizacija genomske nestabilnosti tumora mozga glijalnog porekla. in University of Belgrade, Faculty of Biology. 2013;:1-140.
https://hdl.handle.net/21.15107/rcub_nardus_2160 .

Milinković, Vedrana, "Detekcija i karakterizacija genomske nestabilnosti tumora mozga glijalnog porekla" in University of Belgrade, Faculty of Biology (2013):1-140,
https://hdl.handle.net/21.15107/rcub_nardus_2160 .