人类肿瘤中异常 DNA 甲基化的泛癌症全景

Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors.

机构信息

Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), University of Lausanne (UNIL), Lausanne, Switzerland.

出版信息

Cell Rep. 2018 Oct 23;25(4):1066-1080.e8. doi: 10.1016/j.celrep.2018.09.082.

DOI:10.1016/j.celrep.2018.09.082

PMID:30355485

Abstract

The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and promote oncogenic pathways. Here, we designed an algorithmic approach (RESET) to identify aberrant DNA methylation and associated cis-transcriptional changes across >6,000 human tumors. Tumors exhibiting mutations of chromatin remodeling factors and Wnt signaling displayed DNA methylation instability, characterized by numerous hyper- and hypo-methylated loci. Most silenced and enhanced genes coalesced in specific pathways including apoptosis, DNA repair, and cell metabolism. Cancer-germline antigens (CG) were frequently epigenomically enhanced and their expression correlated with response to anti-PD-1, but not anti-CTLA4, in skin melanoma. Finally, we demonstrated the potential of our approach to explore DNA methylation changes in pediatric tumors, which frequently lack genetic drivers and exhibit epigenomic modifications. Our results provide a pan-cancer map of aberrant DNA methylation to inform functional and therapeutic studies.

摘要

癌症相关改变的发现主要集中在遗传变异上。然而，改变的表观基因组有助于转录失调并促进致癌途径。在这里，我们设计了一种算法方法（RESET）来识别超过 6000 个人类肿瘤中异常的 DNA 甲基化和相关的顺式转录变化。表现出染色质重塑因子和 Wnt 信号突变的肿瘤显示出 DNA 甲基化不稳定性，其特征是存在大量超甲基化和低甲基化的基因座。大多数沉默和增强的基因聚集在特定途径中，包括细胞凋亡、DNA 修复和细胞代谢。癌症-种系抗原 (CG) 经常被表观遗传增强，其表达与皮肤黑色素瘤对抗 PD-1 的反应相关，但与抗 CTLA4 无关。最后，我们证明了我们的方法在探索儿科肿瘤中 DNA 甲基化变化的潜力，这些肿瘤通常缺乏遗传驱动因素并表现出表观遗传修饰。我们的研究结果提供了一个泛癌症的异常 DNA 甲基化图谱，为功能和治疗研究提供信息。