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Prognostički značaj mutacija u genima za izocitrat dehidrogenazu 1 (IDH1) i izocitrat dehidrogenazu 2 (IDH2) u akutnoj mijeloidnoj leukemiji sa normalnim kariotipom

Prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations on outcome in acute myeloid leukemia with normal karyotype

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Author
Virijević, Marijana M.
Mentor
Tomin, Dragica
Committee members
Mihaljević, Biljana
Suvajdžić-Vuković, Nada
Đurđević, Predrag
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Abstract
Mutacije u genima za izocitrat dehidrogenazu 1 i 2 (IDH1 i IDH2) su česte rekurentne molekularne promene kod akutne mijeloidne leukemije sa normalnim kariotipom (AMLNK). Uticaj IDH mutacija na kliničke karakteristike i ishod lečenja kod AML-NK su u velikoj meri istražene, ali samo nekoliko studija je pratilo ove mutacije u toku bolesti. Ciljevi: 1) Utvrđivanje učestalosti prisustva IDH1 i IDH2 mutacija kod bolesnika sa AMLNK; 2) Utvrđivanje uticaja prisustva IDH1 i IDH2 mutacija na učestalost i dužinu remisije, ukupno preživljavanje i povezanosti IDH1 i IDH2 mutacija i drugih prognostičkih markera: parametri krvne slike, biohemijski parametri, citološki tip bolesti, imunofenotipska i molekularno-genetska obeležja (FLT3 i NPM1 mutacije); 3) Utvrđivanje stabilnosti IDH1 i IDH2 mutacija u toku bolesti poređenjem uzoraka na početku bolesti sa uzorcima u toku kompletne remisije (KR), odnosno u recidivu bolesti. Materijal i metodologija istraživanja: Uzorci od 110 starijih de novo AML-NK bol...esnika bili su ispitani na IDH1 i IDH2 mutaciju. Ispitana je njihova povezanost sa drugim prognostičkim markerima i ishodom lečenja. Pored toga, praćena je stabilnost ovih mutacija u KR i recidivu. Rezultati: IDH mutacije su nađene kod 25 (23%) bolesnika: IDH1 je imalo 8 (7%) bolesnika, svi od njih su imali IDHR132; IDH2 je imalo 17 (16%) bolesnika (15 IDHR140; 2 IDHR172). IDH+ bolesnici su imali viši broj trombocita (p=0.024), kao i veći procenat blasta u perifernoj krvi (p=0.031) u odnosu na IDH- bolesnike. IDH+ bolesnici su imali nižu stopu KR u poređenju sa IDH- bolesnicima (44% vs 60%, p=0.152), ali to nije bilo statistički značajno. Osim toga, IDH mutacije su imale samo neznatan uticaj na trajanje remisije bez bolesti (IDH+-12 meseci vs IDH--17 meseci; p=0.091), dok je ukupno preživljavanje (OS) IDH+ bolesnika bilo kraće u poređenju sa IDH- bolesnicima (2 vs 7 meseci; p=0.039). Nepovoljan uticaj IDH mutacije na OS je naročito bio očigledan kod bolesnika koji nisu imali NPM1 mutaciju (5 vs 12 meseci, p=0.050). IDH mutacije su ispitivane sekvencionalno kod 19 IDH+ bolesnika koji su bili živi posle indukcije...

Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent recurrent molecular lesions in acute myeloid leukemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. Aim: 1) To determine the frequency of presence of IDH1 and IDH2 mutations in patients with AML-NK; 2) To determine the effect of the presence of IDH1 and IDH2 mutations on duration of remission, overall survival and the association IDH1 and IDH2 mutations and other prognostic markers: blood parameters, the biochemical parameters, cytological disease type, immunophenotypic and molecular-genetic characteristics (FLT3 and NPM1 mutations); 3) To determine the stability IDH1 and IDH2 mutations in the course of the disease by comparing the samples at the start of the disease with samples during complete remission (CR), and in a relapse of the dise...ase. Material and methodes: Samples from 110 adult de novo AML-NK patients were assessed for IDH1 and IDH2 mutations. Their association with other prognostic markers and outcome was analyzed. In addition, we monitored the stability of these mutations during CR and relapse. Results: IDH mutations were found in 25 (23%) patients: IDH1 in 8 (7%), all of them IDHR132; IDH2 in 17 (16%) patients (15 IDHR140; 2 IDHR172). IDH+ patients had higher platelet counts (p=0.024), as well as a higher percentage of peripheral blood blasts (p=0.031) than IDH- patients. They tended to have a lower CR rate compared to IDH- patients (44% vs 60%, p=0.152), but this was not statistically significant. Moreover, IDH mutations had only a slight impact on disease free survival (IDH+-12 months vs IDH--17 months; p=0.091), but overall survival (OS) of our IDH+ patients was shorter in comparison with IDH- patients (2 vs 7 months; p=0.039)...

Faculty:
University of Belgrade, School of Medicine
Date:
29-09-2017
Projects:
  • Rare Diseases:Molecular Pathophysiology, Diagnostic and Therapeutic Modalities and Social, Ethical and Legal Aspects (RS-41004)
Keywords:
IDH1 mutacija / IDH1 mutation / IDH2 mutation / Acute Myeloid Leukemia / Normal Karyotype / IDH2 mutacija / akutna mijeloidna leukemija / normalan kariotip
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URI
http://nardus.mpn.gov.rs/handle/123456789/8883
http://eteze.bg.ac.rs/application/showtheses?thesesId=5354
https://fedorabg.bg.ac.rs/fedora/get/o:16663/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=49507087

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