Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China.
Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Cancer Biol Med. 2020 Nov 15;17(4):937-952. doi: 10.20892/j.issn.2095-3941.2020.0402. Epub 2020 Dec 15.
Epigenetic aberration plays an important role in the development and progression of hepatocellular carcinoma (HCC). However, the alteration of RNA N6-methyladenosine (m6A) modifications and its role in HCC progression remain unclear. We therefore aimed to provide evidence using bioinformatics analysis.
We comprehensively analyzed the m6A regulator modification patterns of 605 HCC samples and correlated them with metabolic alteration characteristics. We elucidated 390 gene-based m6A-related signatures and defined an m6Ascore to quantify m6A modifications. We then assessed their values for predicting prognoses and therapeutic responses in HCC patients.
We identified 3 distinct m6A modification patterns in HCC, and each pattern had distinct metabolic characteristics. The evaluation of m6A modification patterns using m6Ascores could predict the prognoses, tumor stages, and responses to sorafenib treatments of HCC patients. A nomogram based on m6Ascores showed high accuracy in predicting the overall survival of patients. The area under the receiver operating characteristic curve of predictions of 1, 3, and 5-year overall survivals were 0.71, 0.69, and 0.70 in the training cohort, and in the test cohort it was 0.74, 0.75, and 0.71, respectively. M6Acluster C1, which corresponded to hypoactive mRNA methylation, lower expression of m6A regulators, and a lower m6Ascore, was characterized by metabolic hyperactivity, lower tumor stage, better prognosis, and lower response to sorafenib treatment. In contrast, m6Acluster C3 was distinct in its hyperactive mRNA methylations, higher expression of m6A regulators, and higher m6Ascores, and was characterized by hypoactive metabolism, advanced tumor stage, poorer prognosis, and a better response to sorafenib. The m6Acluster, C2, was intermediate between C1 and C3.
HCCs harbored distinct m6A regulator modification patterns that contributed to the metabolic heterogeneity and diversity of HCC. Development of m6A gene signatures and the m6Ascore provides a more comprehensive understanding of m6A modifications in HCC, and helps predict the prognosis and treatment response.
表观遗传改变在肝细胞癌（HCC）的发生和发展中起着重要作用。然而，RNA N6-甲基腺苷（m6A）修饰的改变及其在 HCC 进展中的作用尚不清楚。因此，我们旨在通过生物信息学分析提供证据。
我们全面分析了 605 例 HCC 样本的 m6A 调节因子修饰模式，并将其与代谢改变特征相关联。我们阐明了 390 个基于基因的 m6A 相关特征，并定义了 m6A 评分来量化 m6A 修饰。然后，我们评估了它们在预测 HCC 患者预后和治疗反应中的价值。
我们在 HCC 中鉴定了 3 种不同的 m6A 修饰模式，每种模式都具有不同的代谢特征。使用 m6A 评分评估 m6A 修饰模式可以预测 HCC 患者的预后、肿瘤分期和对索拉非尼治疗的反应。基于 m6A 评分的列线图在预测患者总生存期方面具有较高的准确性。在训练队列中，预测 1、3 和 5 年总生存率的受试者工作特征曲线下面积分别为 0.71、0.69 和 0.70，在测试队列中分别为 0.74、0.75 和 0.71。与低活性 mRNA 甲基化、m6A 调节剂表达降低和 m6A 评分降低相对应的 m6Acluster C1 表现为代谢活性增强、肿瘤分期较低、预后较好和对索拉非尼治疗反应较低。相比之下，m6Acluster C3 的特征是高活性 mRNA 甲基化、m6A 调节剂表达升高和 m6A 评分升高，表现为代谢活性降低、肿瘤分期较高、预后较差和对索拉非尼治疗反应较好。m6Acluster C2 介于 C1 和 C3 之间。
HCC 存在不同的 m6A 调节因子修饰模式，这些模式有助于 HCC 代谢的异质性和多样性。m6A 基因特征和 m6A 评分的发展提供了对 HCC 中 m6A 修饰的更全面的理解，并有助于预测预后和治疗反应。
