Ding Wubin, Feng Guoshuang, Hu Yige, Chen Geng, Shi Tieliu
Center for Bioinformatics and Computational Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Big Data and Engineering Research Center, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Front Cell Dev Biol. 2020 Jan 29;8:20. doi: 10.3389/fcell.2020.00020. eCollection 2020.
Co-occurrence and mutual exclusivity (COME) of DNA methylation refer to two or more genes that tend to be positively or negatively correlated in DNA methylation among different samples. Although COME of gene mutations in pan-cancer have been well explored, little is known about the COME of DNA methylation in pan-cancer. Here, we systematically explored the COME of DNA methylation profile in diverse human cancer. A total of 5,128,332 COME events were identified in 14 main cancers types in The Cancer Genome Atlas (TCGA). We also identified functional epigenetic modules of the zinc finger gene family in six cancer types by integrating the gene expression and DNA methylation data and the frequently occurred COME network. Interestingly, most of the genes in those functional epigenetic modules are epigenetically repressed. Strikingly, those frequently occurred COME events could be used to classify the patients into several subtypes with significant different clinical outcomes in six cancers as well as pan-cancer (-value ≤ = 0.05). Moreover, we observed significant associations between different COME subtypes and clinical features (e.g., age, gender, histological type, neoplasm histologic grade, and pathologic stage) in distinct cancers. Taken together, we identified millions of COME events of DNA methylation in pan-cancer and detected functional epigenetic COME events that could separate tumor patients into different subtypes, which may benefit the diagnosis and prognosis of pan-cancer.
DNA甲基化的共现与互斥性（COME）指的是在不同样本中，两个或更多基因在DNA甲基化方面倾向于呈正相关或负相关。尽管泛癌中基因突变的COME已得到充分研究，但对于泛癌中DNA甲基化的COME却知之甚少。在此，我们系统地探索了多种人类癌症中DNA甲基化图谱的COME。在癌症基因组图谱（TCGA）的14种主要癌症类型中，共鉴定出5,128,332个COME事件。我们还通过整合基因表达、DNA甲基化数据以及频繁出现的COME网络，在六种癌症类型中鉴定了锌指基因家族的功能性表观遗传模块。有趣的是，那些功能性表观遗传模块中的大多数基因在表观遗传上受到抑制。引人注目的是，那些频繁出现的COME事件可用于将六种癌症以及泛癌中的患者分为几种具有显著不同临床结局的亚型（P值≤0.05）。此外，我们在不同癌症中观察到不同的COME亚型与临床特征（如年龄、性别、组织学类型、肿瘤组织学分级和病理分期）之间存在显著关联。综上所述，我们在泛癌中鉴定出数百万个DNA甲基化的COME事件，并检测到可将肿瘤患者分为不同亚型的功能性表观遗传COME事件，这可能有益于泛癌的诊断和预后。
