Predictive significance of circulating histones in hepatocellular carcinoma patients treated with sorafenib

Background: Predictive biomarkers for advanced hepatocellular carcinoma are lacking. EZH2 drives sorafenib resistance through H3K27me3 and is counteracted by SETD2, which catalyzes H3K36me3. The authors tested the predictive power of circulating H3K27me3 and H3K36me3 in advanced hepatocellular carcinoma patients treated with sorafenib. Methods: A total of 80 plasma samples were tested for histone variants by ELISA. Changes from baseline to best response or progressive disease were correlated with patient survival. Results: A higher EZH2/SETD2 ratio predicted worse prognosis in this setting. H3K27me3 and H3K36me3 decreased from baseline to best response. The H3K27me3/H3K36me3 ratio increased from baseline to progressive disease. Higher ratios at best response were associated with shorter progression-free survival. Conclusion: The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced hepatocellular carcinoma. Plain language summary Hepatocellular carcinoma (HCC) is responsible for approximately 10% of all cancer-related deaths worldwide. It is caused mainly by dysmetabolic syndrome, which is the presence of multiple risk factors: abdominal obesity, high blood pressure, hypercholesterolemia and diabetes. The authors aimed to identify new and predictive factors for sorafenib treatment outcomes in advanced HCC patients. The authors enrolled 85 patients who received sorafenib at two Italian oncological institutions, testing their blood for the following epigenetic biomarkers: H3, H3.1 variant, H3K27me3 and H3K36me3. The authors found that H3K27me3 and H3K36me3 decreased from baseline to maximum tumor shrinkage, H3K27me3/H3K36me3 ratio increased from baseline to progressive disease and higher ratios were associated with shorter progression-free survival. The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced HCC, and its role warrants further investigation in different HCC therapeutic strategies.