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De Bortoli, Massimiliano (2009) Alterazioni del genoma e dell'espressione genica nel medulloblastoma: analisi di caratteristiche modulanti l'aggressivitĂ . [Tesi di dottorato]

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Abstract (inglese)

Medulloblastoma is the most frequent malignant brain tumor of childhood. Despite numerous advances, prognosis is still grim for children who present metastases at diagnosis, tumor progression or recurrence. Survivors suffer long-term toxicities, affecting their neuro-cognitive, psychological, and growth potential or endocrine system.
A better understanding of biological mechanisms underlying medulloblastoma malignant transformation and aggressive behavior will improve patients' management and therapeutical strategies.
By cytogenetical characterisation, we identified the most frequent chromosomal copy number aberrations in 71 medulloblastoma. The most frequent lesions involved loss of 17p, 16q, 10q, 8p, or gains of 17q, 7q o 2p. Gain of 8q is significantly associated to worse overall survival (p = 0,0141), but this result was not entirely attributable to MYC amplifications or overexpression. By applying cytogenetical data to gene expression analysis, we identified three 8q-mapped genes whose expression levels were associated to prognosis: Eucaryotic Translation Elongation Factor 1D (EEF1D), Ribosomal Protein L30 (RPL30), Ribosomal Protein S20 (RPS20).
P53 is a ubiquitous protein which directly regulates genome stability, cell fate, cell cycle, and can induce cell differentiation, senescence or apoptosis. P53 is rarely mutated in medulloblastoma, but its pathway is perturbed. TP73 is an onco-suppressor gene that belong to the same superfamily of genes, and the protein retains same of p53 functions. Moreover, p73 is fundamental in central nervous system development. Recently, many different isoforms of p73 have been identified, encoding a full length (Tap73) and many N-terminal truncated proteins (?Np73). We analyzed p73 isoform expression in cella lines and 34 primary medulloblastoma samples and detected higher levels of TAp73 and ?Np73 compared to normal brain tissue. By Kaplan-Meier analysis, we showed that high expression levels of TAp73 are significantly associated to better prognosis. Overexpression of TAp73 and ?Np73 atered cell cycle and induced apoptosis in basal conditions and after cytotoxic treatment.
WIP1, Wild-type p53-induced phosphatase 1, encoder for a phosphatase tha inhibits p53. Its gene maps on 17q22-q23, which is frequently gained in medulloblastoma. We detected high expression levels in medulloblastoma cell lines and 34 primary tumors, and i particolar in those with gain of 17q. Overexpression of WIP1 counteracts p53 functions, protecting cells from apoptosis under basal growth conditions and after in response to chemotherapeutic drug.
In summary, several biological factors influence medulloblastoma aggressive behavior. We showed that gain of 8q, high expression levels of ribosomal proteins and regulation of p53 functions by p73 isoforms and WIP1 may contribute to the malignant tumor behaviour or modulate therapeutical response in medulloblastoma.

Abstract (italiano)

Il medulloblastoma è il più frequente tumore cerebrale maligno. Nonostante miglioramenti importanti, la prognosi dei pazienti affetti è ancora sfavorevole, soprattutto in caso di malattia metastatica o malattia in progressione o in recidiva. Inoltre, la prognosi dei lungo-sopravviventi è pesantemente condizionata dagli effetti collaterali della chemioterapia e della radioterapia. Una miglior comprensione dei meccanismi biologici che sottendono alla trasformazione maligna e al comportamento aggressivo del medulloblastoma potrà  permettere una migliore stratificazione dei pazienti e una modulazione conseguente della terapia.
Il mio lavoro sul medulloblastoma è stato finalizzato alla caratterizzazione citogenetica del tumore, individuando le alterazioni cromosomiche più frequenti, con delezione di 17p, 16q, 10q, 8p, o guadagno di 17q, 7q o 2p. Abbiamo mostrato come il guadagno del braccio lungo del cromosoma 8 (8q) sia significativamente associato alla prognosi (p = 0,0141), ma questo dato non era interamente attribuibile a amplificazioni o espressione di MYC. L'analisi dell'espressione genica di tumori che mostravano guadagno di 8q, ha permesso di individuare tre geni che mappano sulla stessa regione e la cui espressione era significativamente associata alla prognosi: Eucaryotic Translation Elongation Factor 1D (EEF1D), Ribosomal Protein L30 (RPL30), Ribosomal Protein S20 (RPS20).
P53 è una proteina espressa ubiquitariamente in tutte le cellule, e sovrintende al mantenimento dell'integrità  del patrimonio genetico, alla conservazione del programma genetico specifico per ogni singola cellula, al controllo del ciclo cellulare, fino all'induzione dei processi di differenziazione, senescenza, o apoptosi. Nel medulloblastoma p53 è raramente mutata, ma la via di segnale appare perturbato. TP73 appartiene alla famiglia di TP53, e condivide molte delle funzioni proprie di p53. La proteina da esso codificata è essenziale per lo sviluppo del sistema nervoso centrale. Di p73 sono state identificate una isoforma completa (TAp73) e numerose varianti tronche nella porzione amino-terminale (?Np73). Abbiamo analizzato l'espressione di queste isoforme in linee cellulari di medulloblastoma e in 34 tumori primitivi. Sia le linee cellulari stabilizzate, sia i tumori primitivi esprimevano elevati livelli di TAp73 e ?Np73, relativamente ai controlli cerebrali normali. Mediante analisi di Kaplan-Meier, è stato dimostrato un trend favorevole per i pazienti i cui tumori presentavano sovra espressione di TAp73. Inducendo una maggior espressione di TAp73 e ?Np73, abbiamo dimostrato un'alterazione del ciclo cellulare e un'induzione dell'apoptosi in condizioni basali e in risposta all'azione di farmaci citotossici.
WIP1, Wild-type p53-induced phosphatase 1, codifica per una fosfatasi che inibisce p53. Il gene mappa sulla regione 17q22-q23, della quale i medulloblastomi presentano frequentemente guadagno. Abbiamo dimostrato come WIP1 sia sovraespressa nei medulloblastomi primitivi in relazione ai controlli normali, e in particolare come il guadagno di 17q si associ a livelli maggiormente elevati di WIP1. Inducendo una maggior espressione di WIP1, abbiamo dimostrato come, sia in condizioni basali, sia in risposta al trattamento farmacologico, WIP1 antagonizzi l'azione di p53, determinando, così, una minor induzione dell'apoptosi.
In conclusione, numerosi fattori biologici concorrono a determinare il fenotipo aggressivo nel medulloblastoma. Il guadagno di 8q, elevati livelli di proteine ribosomiali e la regolazione negativa dell'azione di p53 possono contribuire a indurre una maggiore aggressività  o una scarsa risposta alla terapia nel medulloblastoma.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rosolen, Angelo
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > EMATOONCOLOGIA E IMMUNOLOGIA
Data di deposito della tesi:23 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):Medulloblastoma, CGH, 8q, EEF1D, RPS20, RPL30, p53, p73, Wip1, prognosis
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Pediatria
Codice ID:1350
Depositato il:23 Gen 2009
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