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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-11202022-101402


Thesis type
Tesi di specializzazione (5 anni)
Author
SALANI, FRANCESCA
URN
etd-11202022-101402
Thesis title
Predictive significance of circulating histones in hepatocellular carcinoma patients treated with sorafenib: exploring epigenetics in treatment tailoring
Department
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Course of study
ONCOLOGIA MEDICA
Supervisors
relatore Prof. Masi, Gianluca
correlatore Dott. Crea, Francesco
Keywords
  • advanced HCC
  • epigenetics
  • EZH2
  • H3K27me3/H3K36me3 ratio
  • histone post-translational modifications (HPTMs)
  • SETD2
  • treatment prediction
Graduation session start date
10/01/2023
Availability
Withheld
Release date
10/01/2093
Summary
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.
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