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Zattra, Edoardo (2011) Analisi di polimorfismi genetici del gene TP53 e del gene EGF in pazienti con nevi melanocitici multipli. [Tesi di dottorato]

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Abstract (inglese)

Background: p53 have been extensively reported in the literature to be able to modify the activity of melanocytes, particularly in controlling the proliferation of these cells. P53 is a transcriptional activator of genes encoding for proteins that influence the proliferation of melanocytes and in this way the onset and progression of malignant melanoma. Epidermal Growth Factor (EGF) is a growth factor member of the EGF superfamily. It has been shown that it activates cell proliferation and stimulates mitogenesis in epidermal tissue, enhancing tumor growth. The presence of more than 100 nevi has been demonstrated to be a major risk factor for developing malignant melanoma.

Aim of the study: Several experimental data indicate that the two genetic polymorphism of EGF and P53 (IVS6 +62 G> A in intron 6 of TP53 and EGF +61A>G) could play a role in the onset and progression of several neoplasms. We studied the above-mentioned gene polymorphisms in a population of patients with more than 100 melanocytic nevi. Patients were carefully selected on the basis of an accurate clinical and dermatoscopic examination.

Materials and methods: As regards the IVS6 +62 G> A in intron 6 of TP53 polymorphism 98 patients and 117 controls were investigated while for the EGF +61A>G polymorphism we included in the study 128 patients and 127 controls. Patients were all aged between 21 and 60 years and had an high number of melanocytic nevi (>100). Controls were patients with a low number of nevi (< 10) of the same sex and age. For the analysis of the polymorphisms DNA was extracted from peripheral blood and genotyped by High Resolution Melt Analysis (HRM).

Results:
For p53, the genotype (A/A) was present in 4.2% of the patients against a rate of 1.9% in controls. Genotype G/A was significantly increased in patients (32.5%) compared to controls (23.6%). With regard to allele frequencies, G allele was present in 79.6% of patients and 86.3% of controls whereas A allele was present in 20,4% of patients and 13.7% of controls. For EGF, genotype AA was present in 35% of patients and 38% of controls. Genotype A/G was present in 48% of patients and 44% of controls while genotype G/G was present in 17% of patients and 18% of controls. With regard to allele frequency, A was present in 59% of patients and in 60% of controls, whereas G was observed in 41% of patients and 40% of controls.

Conclusions: The polymorphism IVS6 +62 G> A of the TP53 gene was associated with the presence of more than 100 melanocytic nevi indicating that alterations in p53 expression, even if minimal as in this polymorphism, could cause an altered control of melanocytic proliferation that clinically reflects in an high number of melanocytic nevi. There was no significative correlation between the EGF +61A>G polymorphism and the presence of a high number of melanocytic nevi.

Abstract (italiano)

Background: p53 è in grado di modificare l’attività dei melanociti, in particolare la proliferazione di queste cellule. P53 è un attivatore della trascrizione di geni che codificano per proteine con azione stimolatoria sulla proliferazione dei melanociti, pertanto in questo modo p53 può favorire l’insorgenza e la progressione del melanoma maligno. L'Epidermal Growth Factor (EGF) è un fattore di crescita membro della superfamiglia EGF. E’ stato dimostrato che l'EGF attiva la proliferazione cellulare e stimola la mitogenesi nel tessuto cutaneo, stimolando la crescita tumorale. E’ stato dimostrato che la presenza di più di 100 nevi melanocitici è un fattore di rischio importante per la comparsa del melanoma maligno.

Scopo dello studio: I polimorfismi genetici presi in esami in questo studio (IVS6 +62 G> A all’introne 6 di TP53 ed EGF +61A>G e) secondo numerosi studi potrebbero giocare un ruolo nell’insorgenza e nella progressione di diverse neoplasie. Abbiamo analizzato i suddetti polimorfismi in una popolazione di pazienti con più di 100 nevi melanocitici mettendo tali dati a confronto con una popolazione di controllo con meno di 10 nevi melanocitici. Tali pazienti sono stati accuratamente selezionati attraverso esami clinici e dermatoscopici.

Materiali e Metodi: Per lo studio di p53 abbiamo incluso 98 pazienti e 117 controlli, mentre per lo studio dell' EGF abbiamo incluso 128 pazienti e 127 controlli tutti di età compresa tra i 21 e i 60 anni. I pazienti presentavano più di 100 nevi melanocitici di dimensioni superiori a 3 millimetri di diametro. I controlli erano soggetti con meno di 10 nevi melanocitici. Per l’analisi del polimorfismo il DNA è stato estratto da sangue periferico e il genotipo è stato studiato mediante High Resolution Melt Analysis (HRM).

Risultati: Il genotipo A/A di p53, era presente nel 4.2% dei pazienti contro il 1.9% dei controlli. Il genotipo G/A era significativamente maggiore nei pazienti (32.5%) che nei controlli (23.6%). Per quanto riguarda le frequenze alleliche, l’allele G era presente nel 79.6% dei pazienti e nel 86.3% dei controlli mentre l’allele A era presente nel 20,4% dei pazienti e nel 13,7% dei controlli. Per quanto riguarda EGF, il genotipo A/A era presente nel 35% dei pazienti e nel 38% dei controlli. Il genotipo A/G era presente nel 48% dei pazienti e nel 44% dei controlli mentre il genotipo G/G era presente nel 18% dei pazienti e nel 17% dei controlli. Per quanto riguarda la frequenza allelica, A era presente nel 59% dei pazienti e nel 60% dei controlli, mentre G era presente nel 41% dei pazienti e nel 40% dei controlli.

Conclusioni: non è stata rilevata una correlazione significativa tra il polimorfismo EGF +61A>G e la presenza di un alto numero di nevi melanocitici. Il polimorfismo IVS6 +62 G> A del gene TP53 sembra invece essere associato con la presenza di un elevato numero di nevi melanociti essendo la frequenza di questo polimorfismo significativamente maggiore nei casi rispetto ai controlli. E’ plausibile che alterazioni dell’espressione della p53, sia pur minime come quelle osservabili nei polimorfismi genetici che coinvolgono regioni regolatorie del DNA, possano essere responsabili di un alterato controllo della proliferazione melanocitaria che si traduce clinicamente in un alto numero di nevi melanocitici.

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Tipo di EPrint:Tesi di dottorato
Relatore:ALAIBAC, MAURO
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > MALATTIE RARE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:25 Gennaio 2011
Parole chiave (italiano / inglese):polimorfismi, p53, EGF, nevi melanocitici, melanoma maligno. polymorphisms, p53, EGF, melanocytic nevi, malignant melanoma
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/03 Genetica medica
Area 06 - Scienze mediche > MED/35 Malattie cutanee e veneree
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Pediatria
Dipartimenti > pre 2012 - Dipartimento di Scienze Mediche e Chirurgiche
Codice ID:3308
Depositato il:21 Lug 2011 10:37
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