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