DNA甲基化在细胞身份的建立和维持中起着至关重要的作用。然而，在肿瘤发展过程中，DNA甲基化经常发生失调，并与其他遗传变异密切相关。在本研究中，我们利用对687个肾脏、脑、胰腺、肺、头颈部和子宫内膜的肿瘤和与其相邻的非受累组织进行多组学分析，鉴定与RNA和蛋白质丰度变化相关的异常甲基化，并构建了一个Pan-Cancer目录。我们发现了与细胞系特异性表观遗传调控相关的驱动基因，包括子宫内膜癌中的低甲基化FGFR2。我们显示高甲基化STAT5A与广泛的区域调控下调和免疫细胞耗尽相关，这表明STAT5A表观遗传调控在鳞状肿瘤的免疫抑制中构成了一个分子开关。我们进一步证明了甲基化亚型富集信息可以解释起源细胞、肿瘤内部异质性和肿瘤表型。总体而言，我们鉴定了驱动转录和翻译变化的顺式作用DNA甲基化事件，揭示了肿瘤表观遗传景观及其起源细胞的作用。版权所有 © 2023年作者。Elsevier Inc.保留所有权利。

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.