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

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...

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Detalles Bibliográficos
Autores: Liang, Wen-Wei|||0000-0001-7700-8973, Lu, Rita Jui-Hsien Lu, Jayasinghe, Reyka G., Foltz, Steven M., Porta-Pardo, Eduard|||0000-0001-7900-4239, Geffen, Yifat, Wendl, Michael C.|||0000-0002-5694-2668, Lazcano, Rossana, Kolodziejczak, Iga, Song, Yizhe|||0000-0001-8760-6432, Govindan, Akshay, Demicco, Elisabeth G., Li, Xiang, Li, Yize|||0000-0003-1074-281X, Sethuraman, Sunantha, Payne, Samuel H., Fenyö, David, Rodriguez, Henry, Wiznerowicz, Maciej, Shen, Hui, Mani, D.R., Rodland, Karin D., Lazar, Alexander J., Robles, Ana I., Ding, Li|||0000-0003-1517-2975
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:289390
Acceso en línea:https://ddd.uab.cat/record/289390
https://dx.doi.org/urn:doi:10.1016/j.ccell.2023.07.013
Access Level:acceso abierto
Palabra clave:DNA Methylation
Endometrial Neoplasms
Epigenesis, Genetic
Female
Gene Expression Regulation, Neoplastic
Humans
Multiomics
Descripción
Sumario: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.

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