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Molecular-genetic mechanisms of resistance in the prognosis of patients with multiple myeloma

dc.contributor.advisorBila, Jelena
dc.contributor.otherMihaljević, Biljana
dc.contributor.otherTodorović, Milena
dc.contributor.otherPavlović, Sonja
dc.creatorSretenović, Aleksandra M.
dc.date.accessioned2019-02-08T15:49:32Z
dc.date.available2019-02-08T15:49:32Z
dc.date.issued2018-09-19
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6581
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:19365/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50765071
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/10734
dc.description.abstractMultipli mijelom (MM) je bolest za koju se vezuje visok stepen genomske nestabilnosti. Karakteriše se numeričkim i strukturnim hromozomskim aberacijama, koje zauzimaju centralno mesto u prognoznom profilu bolesnika sa MM. Cilj: Utvrditi uticaj postojanja molekularno-genetičkih aberacija: del1p, +1q21, translokacije t(4;14), t(14;16) i del 17p na terapijski odgovor i preživljavanje bolesnika sa multiplim mijelomom. Utvrditi uticaj ekspresije cereblona (CRBN), MDR (multidrug resitance protein) i LRP (lung resistance protein) na terapijski odgovor i preživljavanje bolesnika sa multiplim mijelomom. Metod: Ispitivana su 92 novootkrivena bolesnika sa multiplim mijelomom, koji su dijagnostikovani i lečeni u Klinici za hematologiju KCS u periodu od decembra 2011. do januara 2014. godine. Molekularno-genetička ispitivanja koja su predmet ovog istraživanja su sprovedena u Laboratoriji za citogenetiku i molekularnu genetiku Klinike za hematologiju Kliničkog centra Srbije i u Institutu za molekularnu genetiku i genetičko inženjerstvo (IMGG) u Beogradu. Prisustvo viskorizičkih citogenetskih abnormalnosti utvrđivano je metodom interfazne in situ hibridizacije (iFISH), a nivo ekspresije CRBN, MDR i LRP kod naših ispitanika utvrđivan je metodom „real-time“ PCR. Rezultati: Metodom iFISH prisustvo visokorizičnih citogenetskih abnormalnosti: t (4;14), t(14;16), del 17p utvđeno je kod 14 (15,2%) bolesnika. Kod 27 (29,3%) bolesnika utvrđeno je prisustvo abnormalnosti hromozoma 1. Kod 8 (8,7%) bolesnika delecija 1p, a kod 19 (20,6%) dodatne kopije hromozoma 1q. Kod 4 (4,34%) bolesnika bila je prisutna hiperdiploidija +1q. Bolesnici sa abnormalnostima hromozoma 1 su se karakterisali kraćim trajanjem remisije na granici statističke značajnosti i jasno kraćim preživljavanjem u odnosu na bolesnike bez ovih abnormalnosti. Medijana ekspresije CRBN kod bolesnika sa MM je bila značajno viša u odnosu na zdravu kontrolu. Korelacija izmedju visoke ekspresije CRBN i povoljnog terapijskog odgovora bila je prisutna u grupi bolesnika koji su lečeni talidomidom, što je u skladu sa podacima iz literature, te visoka ekspresija CRBN može da posluži kao surogat marker za bolest niskog rizika. Analiza nivoa ekspresije RQ_MDR1 pokazala je da je njena vrednost bila niža kod bolesnka koji su reagovali na lečenje 252.1±46.2 u odnosu na one koji su umrli 493.8±168, ali T testom nije postignuta statistička značajnost (p=0,233). Slični rezultati su dobijeni i kod RQ_LRP 181.9±31.5 prema 242.5±33.8, takođe bez postizanja statističke značajnosti (p=0,213)...sr
dc.description.abstractMultiple myeloma (MM) is a disease that is associated with a high degree of genomic instability. It is characterized by numerical and structural chromosomal aberrations, which occupy a central place in the prognosis profile of patients with MM. Aim: To determine the influence of the existence of molecular-genetic aberrations: del1p, + 1q21, translocation t (4; 14), t (14; 16) and del 17p on the therapeutic response and survival of patients with multiple myeloma. Determine the effect of cereblone expression (CRBN), MDR (multidrug resistance protein) and LRP (lung resistance protein) on the therapeutic response and survival of patients with multiple myeloma. Method: 92 newly discovered patients with multiple myeloma, who were diagnosed and treated in the Clinic of Hematology of the Clinical Centre of Serbia in the period from December 2011 to January 2014, were examined. Molecular-genetic studies that are the subject of this research were conducted at the Laboratory for Cytogenetics and Molecular Genetics of the Clinic of Hematology of the Clinical Center of Serbia and the Institute for Molecular Genetics and Genetic Engineering (IMGG) in Belgrade. The presence of high-risk cytogenetic abnormalities was determined by interphase in situ hybridization (iFISH), and the level of expression of CRBN, MDR and LRP in our subjects was determined by the method of "real-time" PCR. Results: The iFISH method of presence of high-risk cytogenetic abnormalities: t (4; 14), t (14; 16), del 17p was found in 14 (15.2%) patients. In 27 (29.3%) patients, the presence of abnormalities of chromosome 1 was determined. In 8 (8.7%) patients deletion 1p, and in 19 (20.6%) additional copies of chromosomes 1q. In 4 (4.34%) patients, hyperdiploidy + 1q was present. Patients with abnormalities of chromosome 1 were characterized by shorter duration of remission at the boundary of statistical significance and clearly shorter survival compared to patients without these abnormalities. Median expression of CRBN in patients with MM was significantly higher in relation to healthy control. Correlation between high expression of CRBN and favorable therapeutic response was present in the group of patients treated with thalidomide, which is in accordance with literature data, and high expression of CRBN can serve as a surrogate marker for low-risk disease. Analysis of the expression level RQ_MDR1 showed that its value was lower in patients who responded to treatment 252.1 ± 46.2 compared to those who died 493.8 ± 168, but did not achieve statistical significance with the T test (p = 0.233). Similar results were obtained in RQ_LRP 181.9 ± 31.5 versus 242.5 ± 33.8, also without statistical significance (p = 0.213)...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Медицински факултетsr
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectmultipli mijelom, molekularno-genetički profil, prognozasr
dc.subjectmultiple myeloma, molecular-genetic profile, prognosisen
dc.titleMolekularno-genetički mehanizmi rezistencije u prognozi bolesnika sa multiplim mijelomomsr
dc.title.alternativeMolecular-genetic mechanisms of resistance in the prognosis of patients with multiple myelomaen
dc.typePhD thesis


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