Investigations into the function of nonpromoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated nonpromoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we examined 32 tumor types and identified 57 tumor suppressors and oncogenes out of 260 genes exhibiting a correlation of > 0.5 between gene body methylation and gene expression in at least one tumor type. The lymphocyte-specific gene CARD11 exhibits robust association between gene body methylation and expression across 19 of 32 tumor types examined. It is significantly overexpressed in kidney renal cell carcinoma (KIRC) and lung adenocarcinoma (LUAD) tumor tissues in comparison with respective control samples; and is significantly associated with lower overall survival in KIRC. Contrary to its canonical function in lymphocyte NFκB activation, CARD11 activates the mTOR pathway in KIRC and LUAD, resulting in suppressed autophagy. Furthermore, demethylation of a CpG island within the gene body of CARD11 decreases gene expression. Collectively, our study highlights how DNA methylation outside the promoter region can impact tumor progression. Implications: Our study describes a novel regulatory role of gene body DNA methylation–dependent CARD11 expression on mTOR signaling and its impact on tumor progression.

中文翻译：

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淋巴细胞特异性基因 CARD11 的基因体甲基化导致其过度表达并调节癌症 mTOR 信号转导

对非启动子 DNA 甲基化功能的研究为基因表达的表观遗传调控带来了新的见解。先前的研究强调了区分离散功能区域中 DNA 甲基化的重要性；然而，尚未对多种肿瘤类型和相应的正常组织进行整合的非启动子 DNA 甲基化和基因表达分析。通过基因表达和 DNA 甲基化谱的综合分析，我们检查了 32 种肿瘤类型，并从 260 个基因中鉴定出 57 个抑癌基因和癌基因，在至少一种肿瘤类型中，基因体甲基化与基因表达之间的相关性 > 0.5。淋巴细胞特异性基因 CARD11 在所检查的 32 种肿瘤类型中的 19 种中表现出基因体甲基化和表达之间的紧密关联。与各自的对照样本相比，它在肾肾细胞癌（KIRC）和肺腺癌（LUAD）肿瘤组织中显着过表达；并且与 KIRC 较低的总生存率显着相关。与其在淋巴细胞 NFκB 激活中的典型功能相反，CARD11 激活 KIRC 和 LUAD 中的 mTOR 通路，从而抑制自噬。此外，CARD11 基因体内 CpG 岛的去甲基化会降低基因表达。总的来说，我们的研究强调了启动子区域外的 DNA 甲基化如何影响肿瘤进展。意义：我们的研究描述了基因体 DNA 甲基化依赖性 CARD11 表达对 mTOR 信号传导的新调节作用及其对肿瘤进展的影响。