Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors
Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors
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DOI：
10.1016/j.celrep.2018.09.082
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发表时间：
2018-10-23
期刊：
影响因子：
8.8
通讯作者：
Ciriello, Giovanni
中科院分区：
文献类型：
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作者：
Saghafinia, Sadegh;Mina, Marco;Ciriello, Giovanni
癌症相关改变的发现主要集中在遗传变异上。尽管如此，改变的表观基因组有助于解除转录调控并促进致癌途径。在这里，我们设计了一种算法方法（algorithmic approach）来识别超过6,000种人类肿瘤中的异常DNA甲基化和相关的顺式转录变化。显示染色质重塑因子和Wnt信号转导突变的肿瘤显示DNA甲基化不稳定性，其特征在于许多高甲基化和低甲基化位点。大多数沉默和增强的基因在特定的途径中结合，包括细胞凋亡，DNA修复和细胞代谢。在皮肤黑色素瘤中，癌胚系抗原（CG）经常表观基因组学增强，并且其表达与抗PD-1而非抗CTLA 4的应答相关。最后，我们证明了我们的方法探索儿科肿瘤中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基因组修饰。我们的研究结果提供了一个异常DNA甲基化的泛癌症图谱，为功能和治疗研究提供信息。
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-germ line 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.