Integrative epigenetic and genetic pan-cancer somatic alteration portraits

Genetic and epigenetic alterations are required for carcinogenesis and the mutation burden across tumor types has been investigated. Here, we investigate epigenetic alterations with a novel measure of global DNA methylation dysregulation, the methylation dysregulation index (MDI), across 14 cancer types in The Cancer Genome Atlas (TCGA) database. DNA methylation data—obtained using Illumina HumanMethylation450 BeadChip—was accessed from TCGA. We calculated the MDI in 14 tumor types (n = 5,592 tumors), using adjacent normal tissues (n = 701) from each tumor site. Copy number alteration, and mutation burden were retrieved from cBioportal (n = 5,152). We tested the relation of subject MDI across tumors and with age, gender, tumor stage, estimated tumor purity, and copy number alterations for both overall MDI and genomic-context-specific MDI. We also investigated the top most dysregulated loci shared across tumor types. There was a broad range of extent in methylation dysregulation across tumor types (<i>P</i> &lt; 2.2E-16). However, a consistent pattern of methylation dysregulation stratified by genomic context was observed across tumor types where the highest dysregulation occurred at non-CpG island regions. Considering other summary measures of somatic alteration, MDI was correlated with copy number alterations but not with mutation burden. Using the top dysregulated CpG sites in common across tumors, 4 classes of cancer types were observed, and the functional consequences of these alterations to gene expression were confirmed. This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas. The most dysregulated loci across cancer types identified common clusters across cancer types that may have implications for future treatment and prevention measures.

遗传改变与表观遗传改变是肿瘤发生的必要条件，跨肿瘤类型的突变负荷已得到广泛研究。本研究基于癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中的14种肿瘤类型数据，采用一种全新的全局DNA甲基化紊乱评估指标——甲基化紊乱指数（methylation dysregulation index, MDI），对表观遗传改变展开探究。本研究通过Illumina HumanMethylation450 BeadChip技术获取DNA甲基化数据，数据来源于TCGA数据库。我们针对14种肿瘤类型（共5592例肿瘤样本）计算了MDI，以每个肿瘤位点的配对正常组织（共701例）作为参照。拷贝数改变与突变负荷数据从cBioPortal数据库调取（有效样本量n=5152）。我们分别针对整体MDI与基因组背景特异性MDI，分析了肿瘤受试者的MDI与年龄、性别、肿瘤分期、估计肿瘤纯度及拷贝数改变之间的关联。此外，我们还探究了跨肿瘤类型共有的紊乱程度最高的基因座。跨肿瘤类型的甲基化紊乱程度跨度极大（P < 2.2×10^-16）。但所有肿瘤类型均观察到按基因组背景分层的甲基化紊乱模式：非CpG岛区域的甲基化紊乱程度最高。结合体细胞改变的其他汇总指标来看，MDI与拷贝数改变呈显著相关，但与突变负荷无明显关联。基于跨肿瘤共有的紊乱程度最高的CpG位点，我们将肿瘤类型划分为4个类别，并证实了这些改变对基因表达的功能性影响。本研究明确了14种肿瘤类型的全局DNA甲基化紊乱模式，其中非CpG岛区域受影响程度更高。本研究鉴定出的跨肿瘤类型紊乱程度最高的基因座形成了跨肿瘤的共有聚类，这一发现可为未来的肿瘤治疗与预防策略提供参考依据。