Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
EBioMedicine. 2019 Sep;47:128-141. doi: 10.1016/j.ebiom.2019.08.064. Epub 2019 Sep 4.
CpG island methylator phenotype (CIMP), a common biological phenomenon characterized by a subset of concurrently methylated genes, can have an influence on the progression of multiple cancers. However, the potential mechanism of CIMP in hepatocarcinogenesis and its clinical relevance remains only partially understood.
We used a methylation array from the cancer genome atlas (TCGA) to stratify HCC patients into different CIMP subtypes, and evaluated their correlation with clinical characteristics. In addition, mutation, CNV, and transcriptome profiles were also utilized to evaluate the distinctive genomic patterns correlated with CIMP. Finally, a CIMP-associated prognostic model (CPM) was trained and validated using four independent datasets.
A subgroup of patients was identified as having CIMP-H, which was associated with worse OS and DFS. Gene enrichment analysis indicated that the terms "liver cancer with EPCAM up", "tumor invasiveness up", "methyltransferase complex", and "translational initiation" were enriched in CIMP-H subgroup. Notably, somatic mutation analysis indicated that CIMP-H patients presented with a higher mutation burden of BRD4, DDIAS and NOX1. Moreover, four CPM associated genes could significantly categorize patients into low- and high-risk groups in the training dataset and another 3 independent validation datasets. Finally, a nomogram incorporating a classifier based on four mRNAs, pathological M stage and CIMP status was established, which showed a favorable discriminating ability and might contribute to clinical decision-making for HCC.
Our work highlights the potential clinical application value of CPM in predicting the overall survival of HCC patients and the mechanisms underlying the role of CIMP in hepatocarcinogenesis. FUND: This work was supported by the State Key Project on Infectious Diseases of China (2018ZX10723204-003), the National Nature Science Foundation of China (Nos. 81874065, 81500565, 81874149, 81572427, and 81401997), the Hepato-Biliary-Pancreatic Malignant Tumor Investigation Fund of Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH11800001-2018356).
CpG 岛甲基化表型（CIMP）是一种常见的生物学现象，其特征是一组同时发生甲基化的基因，可能影响多种癌症的进展。然而，CIMP 在肝癌发生中的潜在机制及其临床相关性仍部分未知。
我们使用癌症基因组图谱（TCGA）中的甲基化阵列将 HCC 患者分为不同的 CIMP 亚型，并评估它们与临床特征的相关性。此外，还利用突变、CNV 和转录组谱来评估与 CIMP 相关的独特基因组模式。最后，使用四个独立数据集训练和验证与 CIMP 相关的预后模型（CPM）。
鉴定出一组患者为 CIMP-H，其与 OS 和 DFS 较差相关。基因富集分析表明，“EPCAM 上调的肝癌”、“肿瘤侵袭性增强”、“甲基转移酶复合物”和“翻译起始”等术语在 CIMP-H 亚组中富集。值得注意的是，体细胞突变分析表明，CIMP-H 患者 BRD4、DDIAS 和 NOX1 的突变负担更高。此外，在训练数据集和另外 3 个独立验证数据集中，四个 CPM 相关基因可以将患者明显分为低风险和高风险组。最后，建立了一个基于四个 mRNAs、病理 M 分期和 CIMP 状态的分类器的列线图，该列线图具有良好的区分能力，可能有助于 HCC 的临床决策。
我们的工作强调了 CPM 在预测 HCC 患者总体生存率方面的潜在临床应用价值及其在肝癌发生中的作用机制。
本工作得到国家传染病重大专项（2018ZX10723204-003）、国家自然科学基金（No.81874065、81500565、81874149、81572427 和 81401997）、陈孝平科技发展基金会肝胆胰恶性肿瘤研究基金（CXPJJH11800001-2018356）的资助。
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