Promjene u strukturi gena i izraženosti proteina DVL-1, DVL-2, DVL-3 te transkripcijskih faktora TCF-1 i LEF-1 u astrocitnim tumorima mozga [Changes in gene structure and protein expression of DVL-1, DVL-2, DVL-3 and transcription factors TCF-1 and LEF-1 in astrocytic brain tumors]

Kafka, Anja (2017) Promjene u strukturi gena i izraženosti proteina DVL-1, DVL-2, DVL-3 te transkripcijskih faktora TCF-1 i LEF-1 u astrocitnim tumorima mozga [Changes in gene structure and protein expression of DVL-1, DVL-2, DVL-3 and transcription factors TCF-1 and LEF-1 in astrocytic brain tumors]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Astrocytomas are the most common primary tumors of the central nervous system. According to the WHO classification, there are four grades of astrocytoma, considering their histology, molecular characteristics and prognosis, where the grade IV (glioblastoma) is the deadliest form and still without effective therapy. The aim of this dissertation was to investigate changes in gene structure and protein expression of Dishevelled family and transcription factors TCF1 and LEF1, the molecular components of the Wnt signaling pathway, in astrocytic brain tumors and compare results with clinical parameters. Four selected microsatellite markers for DVL1 (D1S468 and D1S243), DVL2 (D17S960) and DVL3 (D3S1262) genes have shown a significant number of samples demonstrating MSI and LOH, genetic changes that contribute to the genome instability in cancer. Diffuse astrocytomas (WHO grade II) analyzed with D1S468 (p=0.008) have shown the highest percentage of MSI (53.8%), while LOH was the most common in glioblastoma (31.2%) analysed with D3S1262 (p=0.007). The results obtained on the total sample indicate that the microsatellite instability is constantly present, with a more frequent appearance in lower grades and may be the cause of astrocytoma formation, whereas large deletions are significantly associated with the highest grade and have a role in progression. The levels of DVL1, DVL2 and DVL3 protein expression did not show statistically significant correlation with genetic changes. Nevertheless, statistically significant differences in the number of cells with certain level of expression of a single protein between the grades were observed. Bivariate correlation of all analyzed proteins showed a statistically significant positive correlation between DVL3 and TCF1 (p=0.020), DVL3 and LEF1 (p=0.006), TCF1 and LEF1 (p=0.021), while DVL1 and DVL3 were negatively correlated (p=0.002). DVL1 was also negatively correlated (p<0.001) with astrocytoma grade, while DVL3 (p<0.001), TCF1 (p=0.008) and LEF1 (p<0.001) showed positive correlation with malignancy grade suggesting involvement of these proteins in malignant progression. These results contribute to a better understanding of the molecular profile of astrocytic brain tumors and could serve as molecular markers of progression.

Abstract in Croatian

Astrocitomi su najčešći primarni tumori središnjeg živčanog sustava. Prema klasifikaciji WHO u astrocitnim tumorima postoje 4 gradusa/stupnja malignosti, ovisno o njihovoj histologiji, molekularnim karakteristikama i prognozi, gdje je gradus IV (glioblastom) najsmrtonosniji i još uvijek bez učinkovite terapije. Cilj disertacije bio je istražiti promjene gena i proteina obitelji Dishevelled i čimbenika transkripcije TCF1 i LEF1, molekularnih komponenti signalnog puta Wnt, u astrocitnim tumorima mozga i usporediti rezultate s kliničkim parametrima. Četiri odabrana mikrosatelitna biljega za gene DVL1 (D1S468 i D1S243), DVL2 (D17S960) i DVL3 (D3S1262) pokazala su određen broj uzoraka s MSI i LOH, genskim promjenama koje doprinose stanju nestabilnosti genoma tumorskih stanica. Najveći postotak MSI (53.8%) imali su difuzni astrocitomi analizirani biljegom D1S468 (p=0.008), dok je LOH bio najzastupljeniji kod glioblastoma (31.2%) ispitanih biljegom D3S1262 (p=0.007). Rezultati dobiveni na ukupnom uzorku upućuju da je pojavnost mikrosatelitne nestabilnosti konstantno prisutna kroz graduse s tim da je nešto češća u nižim gradusima te može biti uzrok nastanka astrocitoma, dok su velike delecije značajnije pridružene najvišem gradusu i imaju ulogu u progresiji. Razina izraženosti proteina DVL1, DVL2 i DVL3 nije pokazala statistički značajnu korelaciju s genskim promjenama, no opažene su statistički značajne razlike u broju stanica s određenom izraženošću pojedinog proteina između gradusa. Međusobnom bivarijantnom korelacijom svih analiziranih proteina dobivena je statistički značajna pozitivna korelacija između proteina DVL3 i TCF1 (p=0.020), DVL3 i LEF1 (p=0.006), TCF1 i LEF1 (p=0.021), dok su DVL1 i DVL3 bili negativno korelirani (p=0.002). DVL1 je bio negativno koreliran (p<0.001) s gradusom astrocitoma za razliku od DVL3 (p<0.001), TCF1 (p=0.008) i LEF1 (p<0.001) koji su pokazali pozitivnu koreliraciju sa stupnjem malignosti sugerirajući uključenost ovih proteina u malignu progresiju. Dobiveni rezultati doprinose boljem razumijevanju molekularnog profila astrocitnih tumora mozga te bi mogli poslužiti kao molekularni biljezi progresije.

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