Nestabilita genomu buněk mozkových nádorů. Korelace klinických, morfologických a molekulárně-cytogenetických dat

• Název práce v češtině: Nestabilita genomu buněk mozkových nádorů. Korelace klinických, morfologických a molekulárně-cytogenetických dat
• Název v anglickém jazyce: Brain Tumor Cells Genome Instability. Correlation of clinial, morphological and molecular-cytogenetic data
• Klíčová slova: Gliom – FISH – delece – amplifikace – monosomie – trisomie – polyploidie - celkové přežití
• Klíčová slova anglicky: Glioma – FISH – deletion – amplification – monosomy – trisomy – polyploidy - overall survival
• Akademický rok vypsání: 2011/2012
• Typ práce: disertační práce
• Jazyk práce: čeština
• Ústav: Ústav lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFN (11-00410)
• Vedoucí / školitel: prof. Ing. Kyra Michalová, DrSc.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 15.06.2012
• Datum zadání: 15.06.2012
• Datum potvrzení stud. oddělením: 15.06.2012
• Datum a čas obhajoby: 05.09.2012 09:00
• Místo konání obhajoby: Ústav biologie a lékařské genetiky 1. LF
• Datum odevzdání elektronické podoby: 19.06.2012
• Datum proběhlé obhajoby: 05.09.2012
• Předmět: Obhajoba dizertační práce (B90002)
• Oponenti: doc. RNDr. Marek Minárik, Ph.D.

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Předběžná náplň práce

Mozkové gliomy jsou primární mozkové nádory. Již dříve bylo prokázáno, že v nádorových buňkách mozkových gliomů se vyskytují některé nenáhodné chromosomové aberace. Cílem této práce bylo pomocí fluorescenční in-situ hybridizace (FISH) na vzorcích mozkových nádorů získaných při operaci stanovit frekvenci určených chromosomových aberací pomocí vybraných centromerických a lokus specifických sond a získaná data porovnat s klinickými a morfologickými údaji. V průběhu 6 let jsme získali celkem 270 vzorků, u 264 jsme provedli FISH analýzu pomocí panelu námi zvolených sond. Tyto získané výsledky jsme pak porovnali s histologickou analýzou odebraných vzorků a vybranými klinickými údaji (věk, Karnofsky skóre, rozsah resekce, celkové přežití). V každé skupině jsme stanovili medián a průměrnou dobu přežití, poté jsme u vybraných parametrů sledovali jejich vliv na celkovou dobu přežití pomocí Kaplan-Meierovy analýzy, rovněž jsme vytvořili Coxův regresní model se stanovením rizika příslušného parametru. U difuzních a anaplastických astrocytomů a anaplastických oligodendrogliomů stoupá riziko rychlé progrese a upgradingu na nádor vyššího grade při nálezu jiných aberací (především amplifikace EGFR, delece RB1, monosomie chromosomu 10, trisomie chromosomu 7, delece CDKN2A). Tito pacienti jsou sledováni v kratších časových intervalech. U glioblastomu je polyploidie pozitivním prognostickým ukazatelem, monosomie chromosomu je 10 spojena s horším klinickým průběhem a kratší celkovou dobou přežití. Kombinovaná delece 1p/19q je prognosticky příznivým ukazatelem u nádorů s oligodendrogliální komponentou.

Předběžná náplň práce v anglickém jazyce

Gliomas are brain tumors arising from neuroglia. In most cases astrocytic or oligodendroglial component is the main element of the tumor. Non-random chromosomal abberations are found in tumor cells as was revealed previously. The aim of this study was a fluorescence in-situ hybridisation analysis (FISH) of tissue samples obtained during neurosurgical procedures, determine the frequence of selected chromosomal abberations, further correlation with morphological and clinical data and statistical analysis of the results. During six years 264 tissue samples were gained in which FISH with defined probes was performed. The acquired results were compared with histological analysis and selected clinical data (age, Karnofsky score, extent of resection, overall survival). The whole series was divided into 7 groups by tumor type for further statistical analysis. In every group median and mean survival time was calculated, Kaplan-Meier analysis was focused on influence of selected parameters to overall survival. In some categories Cox regression model was created to achieve a hazard ratio of selected parameters. In WHO Grade II and III tumors the risk of malignant progression and tumor upgrading is significantly higher in comparison with samples where specific abberations were not found (EGFR amplification, CDKN2A and RB1 deletion, monosomy of chromosome 10 and trisomy of chromosome 7). In glioblastoma polyploidy is good prognostic marker, monosomy of chromosome 10 is linked to worse clinical course and shorter overall survival.