Tesi etd-11202022-101402 |
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Tipo di tesi
Tesi di specializzazione (5 anni)
Autore
SALANI, FRANCESCA
URN
etd-11202022-101402
Titolo
Predictive significance of circulating histones in hepatocellular carcinoma patients treated with sorafenib: exploring epigenetics in treatment tailoring
Dipartimento
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Corso di studi
ONCOLOGIA MEDICA
Relatori
relatore Prof. Masi, Gianluca
correlatore Dott. Crea, Francesco
correlatore Dott. Crea, Francesco
Parole chiave
- treatment prediction
- H3K27me3/H3K36me3 ratio
- EZH2
- SETD2
- histone post-translational modifications (HPTMs)
- epigenetics
- advanced HCC
Data inizio appello
10/01/2023
Consultabilità
Non consultabile
Data di rilascio
10/01/2093
Riassunto
Background:
Despite diagnostic and therapeutic progress, advanced hepatocellular carcinoma (HCC) has still a dismal prognosis. Robust predictive biomarkers of treatment outcome are lacking. The epigenetic writer EZH2, which controls gene silencing via histone H3K27me3, drives sorafenib resistance. EZH2 is counteracted by SETD2, which catalyses histone H3K36me3. We aimed to test the predictive value of circulating H3K27me3, H3K36me3 and total histone H3 levels in HCC patients treated with sorafenib.
Methods:
We conducted bioinformatic analyses to investigate the clinical significance of SETD2 and EZH2 expression in HCC. Plasma samples from 80 advanced HCC treated with fist-line sorafenib were tested for H3, H3.1, H3K27me3, and H3K36me3 levels by a newly developed ELISA assay. Circulating histone variations from baseline to best response (BR) or progressive disease (PD) were correlated with patients’ survival.
Results:
Both EZH2 and SETD2 were significantly up-regulated in HCC vs normal tissue and higher EZH2/SETD2 values predicted worse prognosis in HCC TGCA patients treated with sorafenib. Circulating levels of H3K27me3 and H3K36me3 decreased from baseline to BR. The H3K27me3/H3K36me3 ratio increased from baseline to PD. Higher ratios at best response were associated with shorter progression-free survival.
Discussion:
Our results suggest that circulating H3K27me3/H3K36me3 ratio levels act as a predictive biomarker for sorafenib outcome in patients with advanced HCC. Validation of these results in the setting of atezolizumab/bevacizumab first line setting is taking place.
Despite diagnostic and therapeutic progress, advanced hepatocellular carcinoma (HCC) has still a dismal prognosis. Robust predictive biomarkers of treatment outcome are lacking. The epigenetic writer EZH2, which controls gene silencing via histone H3K27me3, drives sorafenib resistance. EZH2 is counteracted by SETD2, which catalyses histone H3K36me3. We aimed to test the predictive value of circulating H3K27me3, H3K36me3 and total histone H3 levels in HCC patients treated with sorafenib.
Methods:
We conducted bioinformatic analyses to investigate the clinical significance of SETD2 and EZH2 expression in HCC. Plasma samples from 80 advanced HCC treated with fist-line sorafenib were tested for H3, H3.1, H3K27me3, and H3K36me3 levels by a newly developed ELISA assay. Circulating histone variations from baseline to best response (BR) or progressive disease (PD) were correlated with patients’ survival.
Results:
Both EZH2 and SETD2 were significantly up-regulated in HCC vs normal tissue and higher EZH2/SETD2 values predicted worse prognosis in HCC TGCA patients treated with sorafenib. Circulating levels of H3K27me3 and H3K36me3 decreased from baseline to BR. The H3K27me3/H3K36me3 ratio increased from baseline to PD. Higher ratios at best response were associated with shorter progression-free survival.
Discussion:
Our results suggest that circulating H3K27me3/H3K36me3 ratio levels act as a predictive biomarker for sorafenib outcome in patients with advanced HCC. Validation of these results in the setting of atezolizumab/bevacizumab first line setting is taking place.
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