ABSTRACT The aim of the study was to evaluate the role and the possible clinical and prognostic significance of the expression of specific microRNAs in 'intestinal-type adenocarcinoma of the sinuses (ITACs). Materials and methods: retrospective cohort study on 31 patients undergoing primary surgery for intestinal-type adenocarcinoma of the paranasal sinuses with initial analysis of the miRNoma by Next Generation Sequencing (NGS) technology on surgical samples of adjacent tumor and healthy tissue From the analysis of the miRnoma, a profile of miRNAs constitutionally deregulated in the tumor and biologically relevant in differentiating healthy tissue from neoplastic tissue has been identified. Among these, based on the expression and the distribution in characteristic clusters of the pathology, 4-miRNAs (miR-34b, miR-192, miR-205, miR-449a) were selected, which were subsequently validated on the population of ITAC patients. In order to evaluate their clinical value, the expression of the 4-miRNAs of ITAC patients has been correlated with the clinical stage of the tumor. In addition, overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier curve and miRNA groups (below and above the median) were compared using the log-rank test. Cox multivariate regression analysis was used to evaluate independent survival prediction factors. A p value of 0.05 was considered statistically significant. All analyzes were performed using SPSS for Windows version 19.0 (SPSS Inc, Chicago, IL). Results: both the expression of miR-205 and miR-449a were significantly related to disease free time (Desease Free Survival). In particular, high levels of the two miRNAs (up-regolation) were associated with a higher risk of recurrence and therefore with a worse prognosis. The multivariate analysis confirms the independent predictive value of the miR-205 and miR-449a. Low levels (down-regulation) of miR-205 or miR-449a correlates with a risk of recurrence, respectively about 11 and 3 times. Conclusions: The present study provides the first evidence that an overexpression of miR-205 and miR-449a in ethmoid intestinal adenocarcinomas (ITAC) is associated with an increased risk of recurrence (reduced disease-free time -Desease Free Survival- DFS) and reduced overall survival (OS), suggesting that mutation of these microRNAs in combination with additional genetic events could play a significant role in the pathogenesis of ITAC.
ABSTRACT Obiettivo dello studio: valutare il ruolo ed il possibile significato clinico-prognostico dell’espressione di specifici microRNAs nell’ adenocarcinoma di tipo intestinale dei seni paranasali (ITACs). Materiali e metodi: studio di coorte retrospettivo su 31 pazienti sottoposti ad intervento chirurgico primario per adenocarcinoma di tipo intestinale dei seni paranasali con iniziale analisi del miRNoma tramite tecnologia Next Generation Sequencing (NGS) sui campioni chirurgici di tessuto tumorale e sano adiacente Dall’analisi del miRnoma è stato identificato un profilo di miRNAs costituzionalmente deregolati nel tumore e biologicamente rilevanti nel differenziare il tessuto sano da quello neoplastico. Tra questi, sulla base dell’espressione e la distribuzione in clusters caratteristici della patologia, sono stati selezionati 4-miRNAs (miR-34b, miR-192, miR-205, miR-449a), i quali sono stati successivamente validati sulla popolazione di pazienti ITAC. Allo scopo di valutarne il valore clinico, l’espressione dei 4-miRNAs dei pazienti ITAC è stata correlata con lo stadio clinico del tumore. Inoltre, la sopravvivenza globale (overall survival, OS) e il tempo libero da malattia (disease-free survival, DFS) sono state analizzate mediante la curva Kaplan-Meier e i gruppi dei miRNA (sotto e sopra la mediana) sono stati confrontati usando il test log-rank. L'analisi di regressione multivariata di Cox è stata utilizzata per valutare i fattori di predizione indipendenti di sopravvivenza. Un valore di p <0.05 è stato considerato statisticamente significativo. Tutte le analisi sono state eseguite utilizzando SPSS per Windows versione 19.0 (SPSS Inc, Chicago, IL). Risultati: sia l’espressione del miR-205 che del miR-449a erano significativamente correlate al tempo libero da malattia (Desease Free Survival). In particolare, elevati livelli dei due miRNAs (up-regolation) erano associati ad un più alto rischio di recidiva e quindi ad una prognosi peggiore. L’analisi multivariata conferma il valore predittivo indipendente del miR-205 e miR-449a. Bassi livelli (down-regolation) di miR-205 o miR-449a si correla ad un rischio di recidiva, rispettivamente di circa 11 e 3 volte. Conclusioni: Il presente studio fornisce la prima evidenza che una iperespressione di miR-205 e miR-449a negli adenocarcinomi di tipo intestinale etmoidale (ITAC) è associata ad un maggior rischio di recidiva (ridotto tempo libero da malattia -Desease Free Survival- DFS) e ad una ridotta sopravvivenza complessiva (Overall Survival - OS), suggerendo che la mutazione di questi microRNAs in combinazione con ulteriori eventi genetici, potrebbe svolgere un ruolo significativo nella patogenesi dell'ITAC.
ANALISI DEL MIRNOMA NELL'ADENOCARCINOMA DI TIPO INTESTINALE NASO-SINUSALE: identificazione di un profilo di miRNAs e significato clinico-prognostico
GIGANTE, MONICA
2019/2020
Abstract
ABSTRACT The aim of the study was to evaluate the role and the possible clinical and prognostic significance of the expression of specific microRNAs in 'intestinal-type adenocarcinoma of the sinuses (ITACs). Materials and methods: retrospective cohort study on 31 patients undergoing primary surgery for intestinal-type adenocarcinoma of the paranasal sinuses with initial analysis of the miRNoma by Next Generation Sequencing (NGS) technology on surgical samples of adjacent tumor and healthy tissue From the analysis of the miRnoma, a profile of miRNAs constitutionally deregulated in the tumor and biologically relevant in differentiating healthy tissue from neoplastic tissue has been identified. Among these, based on the expression and the distribution in characteristic clusters of the pathology, 4-miRNAs (miR-34b, miR-192, miR-205, miR-449a) were selected, which were subsequently validated on the population of ITAC patients. In order to evaluate their clinical value, the expression of the 4-miRNAs of ITAC patients has been correlated with the clinical stage of the tumor. In addition, overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier curve and miRNA groups (below and above the median) were compared using the log-rank test. Cox multivariate regression analysis was used to evaluate independent survival prediction factors. A p value of 0.05 was considered statistically significant. All analyzes were performed using SPSS for Windows version 19.0 (SPSS Inc, Chicago, IL). Results: both the expression of miR-205 and miR-449a were significantly related to disease free time (Desease Free Survival). In particular, high levels of the two miRNAs (up-regolation) were associated with a higher risk of recurrence and therefore with a worse prognosis. The multivariate analysis confirms the independent predictive value of the miR-205 and miR-449a. Low levels (down-regulation) of miR-205 or miR-449a correlates with a risk of recurrence, respectively about 11 and 3 times. Conclusions: The present study provides the first evidence that an overexpression of miR-205 and miR-449a in ethmoid intestinal adenocarcinomas (ITAC) is associated with an increased risk of recurrence (reduced disease-free time -Desease Free Survival- DFS) and reduced overall survival (OS), suggesting that mutation of these microRNAs in combination with additional genetic events could play a significant role in the pathogenesis of ITAC.| File | Dimensione | Formato | |
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Tesi Monica Gigante.pdf
embargo fino al 22/06/2026
Descrizione: Documento di tesi Monica Gigante
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3.44 MB | Adobe PDF |
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https://hdl.handle.net/20.500.12075/2026