TY - JOUR
T1 - Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin
AU - Clinical Proteomic Tumor Analysis Consortium
AU - Liang, Wen Wei
AU - Lu, Rita Jui Hsien
AU - Jayasinghe, Reyka G.
AU - Foltz, Steven M.
AU - Porta-Pardo, Eduard
AU - Geffen, Yifat
AU - Wendl, Michael C.
AU - Lazcano, Rossana
AU - Kolodziejczak, Iga
AU - Song, Yizhe
AU - Govindan, Akshay
AU - Demicco, Elizabeth G.
AU - Li, Xiang
AU - Li, Yize
AU - Sethuraman, Sunantha
AU - Payne, Samuel H.
AU - Fenyö, David
AU - Rodriguez, Henry
AU - Wiznerowicz, Maciej
AU - Shen, Hui
AU - Mani, D. R.
AU - Rodland, Karin D.
AU - Lazar, Alexander J.
AU - Robles, Ana I.
AU - Ding, Li
AU - Aguet, François
AU - Akiyama, Yo
AU - An, Eunkyung
AU - Anand, Shankara
AU - Anurag, Meenakshi
AU - Babur, Ozgun
AU - Bavarva, Jasmin
AU - Birger, Chet
AU - Birrer, Michael
AU - Calinawan, Anna
AU - Cantley, Lewis C.
AU - Cao, Song
AU - Carr, Steve
AU - Ceccarelli, Michele
AU - Chan, Daniel
AU - Chinnaiyan, Arul
AU - Cho, Hanbyul
AU - Chowdhury, Shrabanti
AU - Cieslik, Marcin
AU - Clauser, Karl
AU - Colaprico, Antonio
AU - Hu, Yingwei
AU - Zhang, Hui
AU - Zhang, Zhen
AU - Chan, Daniel W.
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/9/11
Y1 - 2023/9/11
N2 - 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.
AB - 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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U2 - 10.1016/j.ccell.2023.07.013
DO - 10.1016/j.ccell.2023.07.013
M3 - Article
C2 - 37582362
AN - SCOPUS:85169883386
SN - 1535-6108
VL - 41
SP - 1567-1585.e7
JO - Cancer cell
JF - Cancer cell
IS - 9
ER -