Predictive Significance of Circulating Histones in Hepatocellular Carcinoma Patients Treated with Sorafenib

Figures & data

Figure 1. Bioinformatics data on EZH2 and SETD2.

(A) EZH2 and (B)SETD2 expression in HCC and normal tissues. (C)EZH2 and SETD2 co-expressed genes. (D) Functional pathway map of co-expressed EZH2 and SETD2 genes. Correlation of (E)EZH2, (F)SETD2 and (G)EZH2/SETD2 with OS.

***p < 0.05.

HCC: Hepatocellular carcinoma; HR: Hazard ratio; OS: Overall survival; TCGA: The Cancer Genome Atlas.

Table 1. H3, H3.1, H3K27me3, H3K36me3 and H3K27me3/H3K36me3 ratio descriptive statistics at studied time points.

	Baseline	BR	PD
H3 N evaluable Median (95% CI) Mean (95% CI) Range	80 0.45 (0.32–0.79) 0.82 (0.64–1.00) 0.02–3.16	21 0.32 (0.17–0.50) 0.35 (0.25–0.45) 0.037–0.75	24 0.36 (0.21–0.71) 0.65 (0.34–0.97) 0.00–2.75
H3.1 N evaluable Median (95% CI) Mean (95% CI) Range	80 0.50 (0.39–0.63) 0.79 (0.61–0.96) 0.07–3.08	21 0.24 (0.14–0.42) 0.36 (0.15–0.58) 0.00–2.13	24 0.41 (0.27–0.56) 0.52 (0.31–0.74) 0.00–2.37
H3K27me3 N evaluable Median (95% CI) Mean (95% CI) Range	80 0.28 (0.20–0.33) 0.37 (0.28–0.47) 0.00–2.39	21 0.09 (0.06–0.12) 0.11 (0.06–0.16) 0.00–0.48	24 0.13 (0.08–0.32) 0.25 (0.14–0.33) 0.00–0.75
H3K36me3 N evaluable Median (95% CI) Mean (95% CI) Range	80 122.90 (104.70–149.57) 137.38 (117.68–147.09) 0.00–273.34	21 22.90 (6.70–43.23) 22.67 (15.48–39.85) 0.00–100.66	24 19.73 (6.68–55.60) 55.52 (26.64–85.40) 2.34–222.51
(H3K27me3/H3K36me3)*10^3 N evaluable Median (95% CI) Mean (95% CI) Range	78 0.0023 (0.0019–0.0026) 0.0034 (0.0026–0.0042) 0.00–0.153	20 0.0051 (0.003–0.012) 0.0065 (0.0028–0.010) 0.00–0.034	24 0.0032 (0.002–0.008) 0.0067 (0.003–0.001) 0.00–0.340

H3, H3.1 and H3K27me3 values are expressed in μg/ml. H3k36me3 values are expressed in ng/ml. H3K27me3/H3K36me3 ratio is dimensionless.

BR: Best response; PD: Progressive disease.

Table 2. Univariate analysis of overall and progression-free survival and H3, H3.1, H3K27me3, H3K36me3 and H3K27me3/H3K36me3 ratio baseline values.

	mOS, months	p-value	mPFS, months	p-value
H3 Median ≥ vs	14.37 vs 8.82	0.50	4.51 vs 2.93	0.52
H3.1 Median ≥ vs	8.79 vs 12.47	0.10	2.76 vs 4.77	0.11
H3K27me3 Median ≥ vs	9.23 vs 12.27	0.77	3.09 vs 3.62	0.99
H3K36me3 Median ≥ vs	14.60 vs 9.23	0.80	3.85 vs 3.0	0.43
(H3K27me3/H3K36me3)*10^3 Median ≥ vs	8.59 vs 13.0	0.26	2.77 vs 4.90	0.29

H3, H3.1 and H3K27me³ values are expressed in μg/ml. H3K36me³ values are expressed in ng/ml. H3K27me³/H3K36me³ ratio is dimensionless.

mOS: Median overall survival; mPFS: Median progression-free survival.

Figure 2. Epigenetic biomarker variations from baseline to best response or progressive disease.

Variations in (A) H3, (B) H3.1, (C) H3K27me3, (D) H3K36me3 and (E) H3K27me3/H3K36me3 ratio (K27/K36 ratio) from B to BR in responders. Variations in (F) H3, (G) H3.1, (H) H3K27me3, (I) H3K36me3 and (J) H3K27me3/H3K36me3 ratio (K27/K36 ratio) from B to PD in all evaluable patients. (E & J) Because of the high dynamic range of values for the H3K27me3/H3K36me3 ratio plot, a mixed linear/log scale was used for the y-axis. Fold change obtained as median biomarker value at BR or PD/median biomarker value at B. Data compared using Wilcoxon signed-rank or paired t-test.

B: Baseline; BR: Best response; PD: Progressive disease.

Figure 3. Kaplan–Meier curves for progression-free and overall survival according to H3K27me3/H3K36me3 ratio values at best response and progressive disease.

Kaplan–Meier curves for (A) PFS according to H3K27me3/H3K36me3 ratio mean values at BR, (B) OS according to H3K27me3/H3K36me3 ratio mean values at BR and (C) OS according to H3K27me3/H3K36me3 ratio median values at PD. Data for all curves compared using log rank test.

BR: Best response; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival.

Data sharing statement

The datasets used or analyzed in the current study are available from the first author and corresponding author upon reasonable request.