小柯机器人

美国圣路易斯华盛顿大学Li Ding研究组近日取得一项新成果。经过不懈努力，他们利用综合多组学癌症分析揭示出与治疗脆弱性和细胞起源相关的DNA甲基化模式。相关论文于2023年8月14日发表在《癌细胞》杂志上。

研究人员对687个肿瘤进行了多组学分析，并与来自肾脏、脑、胰腺、肺、头颈部和子宫内膜的非受累邻近组织匹配，以鉴定与RNA和蛋白质丰度变化相关的异常甲基化并建立泛癌图谱。研究人员发现了谱系特异性表观遗传驱动因素，包括子宫内膜癌中FGFR2的低甲基化。研究发现STAT5A的高度甲基化与常见调节因子下调和免疫细胞耗竭有关，这表明STAT5A的表观遗传调控是鳞状肿瘤免疫抑制的分子开关。进一步研究表明甲基化亚型的富集信息可以解释起源细胞、肿瘤内异质性和肿瘤表型。

总体而言，该研究确定了驱动转录和翻译变化的顺式作用DNA甲基化事件，揭示了肿瘤的表观遗传景观及其起源细胞的作用。 

研究人员表示，DNA甲基化在确立和维持细胞身份方面起着关键作用。然而，在肿瘤发展过程中DNA甲基化经常失调，并与其他遗传改变紧密交织在一起。

附：英文原文

Title: Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin

Author: Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G. Jayasinghe, Steven M. Foltz, Eduard Porta-Pardo, Yifat Geffen, Michael C. Wendl, Rossana Lazcano, Iga Kolodziejczak, Yizhe Song, Akshay Govindan, Elizabeth G. Demicco, Xiang Li, Yize Li, Sunantha Sethuraman, Samuel H. Payne, David Feny, Henry Rodriguez, Maciej Wiznerowicz, Hui Shen, D.R. Mani, Karin D. Rodland, Alexander J. Lazar, Ana I. Robles, Li Ding, Franois Aguet, Yo Akiyama, Eunkyung An, Shankara Anand, Meenakshi Anurag, Ozgun Babur, Jasmin Bavarva, Chet Birger, Michael Birrer, Anna Calinawan, Lewis C. Cantley, Song Cao, Steve Carr, Michele Ceccarelli, Daniel Chan, Arul Chinnaiyan, Hanbyul Cho, Shrabanti Chowdhury, Marcin Cieslik, Karl Clauser, Antonio Colaprico, Daniel Cui Zhou, Felipe da Veiga Leprevost, Corbin Day, Mohan Dhanasekaran, Marcin Domagalski, Yongchao Dou, Brian Druker, Nathan Edwards, Matthew Ellis, Myvizhi Esai Selvan, Alicia Francis, Gad Getz, Michael A. Gillette, Tania Gonzalez Robles, Sara Gosline, Zeynep Gümü, David Heiman, Tara Hiltke, Runyu Hong, Galen Hostetter, Yingwei Hu, Chen Huang, Emily Huntsman, Antonio Iavarone, Eric Jaehnig, Scott Jewel, Jiayi Ji, Wen Jiang, Jared Lee Johnson, Lizabeth Katsnelson, Karen Ketchum, Karsten Krug, Chandan Kumar-Sinha, Jonathan Lei, Yuxing Liao, Caleb Lindgren, Tao Liu, Wenke Liu, Weiping Ma, Fernanda Martins Rodrigues, Wilson McKerrow, Mehdi Mesri, Alexey I. Nesvizhskii, Chelsea Newton, Robert Oldroyd, Gilbert Omenn, Amanda Paulovich, Francesca Petralia, Pietro Pugliese, Boris Reva, Kelly Ruggles, Dmitry Rykunov, Shankha Satpathy, Sara Savage, Eric Schadt, Michael Schnaubelt, Tobias Schraink

Issue&Volume: 2023-08-14

Abstract: 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.

DOI: 10.1016/j.ccell.2023.07.013

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00253-2

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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