ABSTRACT

Properly stratifying high-risk individuals with early stage hepatocellular carcinoma (HCC) is essential to identify patients in which the potentially therapies can be offered. To this context, we systematically investigated the prognostic value of epigenetic clock with early stage HCC as well as the association with other molecular characteristics.

We computed DNA methylation (DNAm) age of 256 early stage HCC patients and 50 normal samples from TCGA by Horvath clock model. The characteristics of two DNAm age subgroups were differentiated regarding HBV expression, pathway activity, epigenomic, and genomic alteration. Cox regression and restricted cubic spline (RCS) analysis were utilized to evaluate the prognostic value of epigenetic acceleration.

DNAm age was significantly associated with chronological age in normal tissue but largely disrupted in tumors (P< .001), and showed significant negative correlation with HBV expression (P< .05). We identified two DNAm age groups (DNAmAge-ACC and DNAmAge-DEC), and the former presented with an immunoactive phenotype (all FDRs<0.05 in enrichment analysis), CpG island hypermethylation (P< .001), and lower mutation burden (P= .018). Every 10-year increase in DNAm age was associated with a 18% decrease in fatality after adjustment for major clinical variables; DNAmAge-ACC had 50% lower mortality risk than DNAmAge-DEC (HR: 0.50, 95% CI: 0.27–0.94, P= .03). RCS revealed the fatality risk significantly decreased as epigenetic age accelerated (P = .04). Conclusions

In summary, we highlighted the prognostic value of epigenetic age acceleration for early stage HCC; better prognosis, relatively lower HBV load, and higher enrichment of immune signatures were tightly associated with epigenetic age accelerated tumors.

摘要

对患有早期肝细胞癌 (HCC) 的高危个体进行正确分层对于确定可以提供潜在治疗的患者至关重要。在此背景下，我们系统地研究了表观遗传时钟对早期 HCC 的预后价值以及与其他分子特征的关联。

我们通过 Horvath 时钟模型计算了 256 名早期 HCC 患者和 50 名来自 TCGA 的正常样本的 DNA 甲基化 (DNAm) 年龄。两个 DNAm 年龄亚组的特征在 HBV 表达、通路活性、表观基因组和基因组改变方面存在差异。Cox 回归和受限三次样条 (RCS) 分析用于评估表观遗传加速的预后价值。

DNAm 年龄在正常组织中与实际年龄显着相关，但在肿瘤中主要被破坏（P < .001），并且与 HBV 表达呈显着负相关（P < .05）。我们确定了两个 DNAm 年龄组（DNAmAge-ACC 和 DNAmAge-DEC），前者具有免疫活性表型（富集分析中所有 FDR <0.05）、CpG 岛高甲基化（P < .001）和较低的突变负荷（P = .018）。在调整主要临床变量后，DNAm 年龄每增加 10 年，死亡率就会下降 18%；DNAmAge-ACC 的死亡风险比 DNAmAge-DEC 低 50%（HR：0.50，95% CI：0.27–0.94，P= .03）。RCS 显示，随着表观遗传年龄的增加，死亡风险显着降低（P = .04）。结论

总之，我们强调了表观遗传年龄加速对早期 HCC 的预后价值；更好的预后、相对较低的 HBV 载量和更高的免疫特征富集与表观遗传年龄加速的肿瘤密切相关。