Novel Molecular Subtypes Associated With 5mC Methylation and Their Role in Hepatocellular Carcinoma Immunotherapy.
Novel Molecular Subtypes Associated With 5mC Methylation and Their Role in Hepatocellular Carcinoma Immunotherapy.
复制标题
与 5mC 甲基化相关的新型分子亚型及其在肝细胞癌免疫治疗中的作用
DOI：
10.3389/fmolb.2020.562441
复制
发表时间：
2020
影响因子：
5
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Mo Z;Cao Z;Luo S;Chen Y;Zhang S
背景5-甲基胞嘧啶（5-methylcytosine，5 mC）在多种肿瘤的预后中有报道，但其在肝细胞癌（hepatocellular carcinoma，HCC）中的作用尚未研究。本研究旨在鉴定与5 mC相关的分子亚型，并建立相关评分以预测HCC的预后。方法从癌症基因组图谱数据库中检索体细胞基因突变数据和基因表达数据。基于5 mC调节因子的表达，通过无监督聚类来鉴定分子亚型，并且通过存活、突变、基因集变异和免疫细胞浸润分析来研究每个亚型的分子特征。接下来，我们根据新的亚型进行差异表达分析，并选择重叠基因进行进一步分析。采用单因素考克斯分析方法对这些基因进行分析，并通过Lasso回归分析建立预后模型。同时采用生存分析和基因集富集分析分别探讨其预后及相关通路。来自国际癌症基因组联盟数据库的LIRI队列被用作验证5 mC亚型和5 mC评分的参考。结果共检测到21种5 mC调节因子，并鉴定出3种5 mC相关分子亚型。这三种亚型在预后、免疫细胞浸润、免疫检查点抑制剂、信号通路和突变特征方面存在显著差异。与簇3相比，簇2表现出PD-L1、TIM 3、半乳糖凝集素9、CTLA 4和CD 80的表达显著增加，而PD-L1、TIM 3和CD 80在簇2中比在簇1中更高。此外，由7个基因（SGPP 2、SALL 4、B3 GNT 7、ROR 1、MYBL 2、SLC 7A 1和CAND 2）组成的5 mC相关评分被证明与预后显著相关。因此，已确定的亚型和评分通过经验证的队列成功验证。结论本研究首次发现了一种基于5 mC调节子的新型分子亚型。5 mC相关亚型的鉴定有助于揭示5 mC与免疫之间的潜在关系，并为HCC的个体化治疗提供新的见解。
Background 5-methylcytosine (5mC) has been reported in the prognosis of a variety of cancers, however, its role in hepatocellular carcinoma (HCC) has not been investigated yet. This study aimed at identifying the molecular subtypes associated with 5mC and establishing a relevant score to predict its prognosis in HCC. Methods Somatic gene mutation data and gene expression data were retrieved from The Cancer Genome Atlas database. Molecular subtypes were identified by unsupervised clustering based on the expression of 5mC regulators, and the molecular features of each subtype were investigated by survival, mutation, gene set variation, and immune cell infiltration analyses. Next, we performed a differentially expressed analysis based on the new subtypes and selected the overlapping genes for further analysis. We undertook univariate Cox analysis to analyze these genes and constructed a prognostic model by lasso regression analysis. Meanwhile, survival and gene set enrichment analyses were used to explore the prognosis and the relevant pathways, respectively. The LIRI cohort from the International Cancer Genome Consortium database was used as a reference to validate the 5mC subtypes and 5mC score. Results Twenty-one types of 5mC regulators were employed in this study, and three 5mC-associated molecular subtypes were identified. These three subtypes presented significant differences in prognosis, immune cell infiltration, immune checkpoint inhibitors, signaling pathways, and mutational features. Compared with cluster 3, cluster 2 exhibited significantly increased expression of PD-L1, TIM3, Galectin9, CTLA4, and CD80, while PD-L1, TIM3, and CD80 were higher in cluster 2 than in cluster 1. Furthermore, a 5mC-related score, composed of seven genes (SGPP2, SALL4, B3GNT7, ROR1, MYBL2, SLC7A1, and CAND2), was proven to be significantly associated with prognosis. The established subtypes and scores were thus successfully verified by the validated cohort. Conclusion To the best of our knowledge, this is the first study to identify a novel molecular subtype based on 5mC regulators. The identification of the 5mC-associated subtype may help reveal the potential relation between 5mC and immunity and provide novel insights for the development of individualized therapy for HCC.
登录
查看更多内容
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
4.7
作者：
Li, Wenli;Wang, Huimei;Liu, Jun
通讯作者：
Liu, Jun
影响因子：
13.5
作者：
Nishida, Naoshi;Nagasaka, Takeshi;Goell, Ajay
通讯作者：
Goell, Ajay
影响因子：
12.4
作者：
Hlady, Ryan A.;Zhao, Xia;Robertson, Keith D.
通讯作者：
Robertson, Keith D.
影响因子：
15.3
作者：
Linsley, P S;Brady, W;Urnes, M;Grosmaire, L S;Damle, N K;Ledbetter, J A
通讯作者：
Ledbetter, J A