Aberrant DNA methylation is a hallmark of many cancer types. Despite our knowledge of epigenetic and transcriptomic alterations in lung adenocarcinoma (LUAD), we lack robust multi‐modal molecular classifications for patient stratification. This is partly because the impact of epigenetic alterations on lung cancer development and progression is still not fully understood. To that end, we identified disease‐associated processes under epigenetic regulation in LUAD. We performed a genome‐wide expression‐methylation Quantitative Trait Loci (emQTL) analysis by integrating DNA methylation and gene expression data from 453 patients in the TCGA cohort. Using a community detection algorithm, we identified distinct communities of CpG‐gene associations with diverse biological processes. Interestingly, we identified a community linked to hormone response and lipid metabolism; the identified CpGs in this community were enriched in enhancer regions and binding regions of transcription factors such as FOXA1/2, GRHL2, HNF1B, AR, and ESR1. Furthermore, the CpGs were connected to their associated genes through chromatin interaction loops. These findings suggest that the expression of genes involved in hormone response and lipid metabolism in LUAD is epigenetically regulated through DNA methylation and enhancer‐promoter interactions. By applying consensus clustering on the integrated expression‐methylation pattern of the emQTL‐genes and CpGs linked to hormone response and lipid metabolism, we further identified subclasses of patients with distinct prognoses. This novel patient stratification was validated in an independent patient cohort of 135 patients and showed increased prognostic significance compared to previously defined molecular subtypes.

中文翻译：

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多组学分析揭示肺腺癌的表观遗传调控过程和患者分类

异常 DNA 甲基化是许多癌症类型的标志。尽管我们了解肺腺癌（LUAD）的表观遗传和转录组学改变，但我们缺乏用于患者分层的可靠的多模式分子分类。部分原因是表观遗传改变对肺癌发生和进展的影响尚未完全了解。为此，我们确定了 LUAD 中表观遗传调控下的疾病相关过程。我们通过整合 TCGA 队列中 453 名患者的 DNA 甲基化和基因表达数据，进行了全基因组表达甲基化定量性状位点 (emQTL) 分析。使用群落检测算法，我们识别了与不同生物过程相关的 CpG 基因的不同群落。有趣的是，我们发现了一个与激素反应和脂质代谢相关的群落；该群落中已鉴定的 CpG 富集于 FOXA1/2、GRHL2、HNF1B、AR 和 ESR1 等转录因子的增强子区域和结合区域。此外，CpG 通过染色质相互作用环与其相关基因连接。这些发现表明，LUAD 中涉及激素反应和脂质代谢的基因表达通过 DNA 甲基化和增强子-启动子相互作用进行表观遗传调节。通过对与激素反应和脂质代谢相关的 emQTL 基因和 CpG 的整合表达甲基化模式应用共识聚类，我们进一步确定了具有不同预后的患者亚类。这种新的患者分层在 135 名患者的独立患者队列中得到了验证，与之前定义的分子亚型相比，显示出更高的预后意义。