(Washington University in St. Louis)
(Washington University in St. Louis)
(Washington University in St. Louis)
(Washington University in St. Louis)
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
| Data: |
2023 |
| Resum: |
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. |
| Nota: |
We thank InPrint for the editing, Matthew A. Wyczalkowski for feedback on figures, and BioRender for diagrams. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) is supported by the National Cancer Institute of the National Institutes of Health under award numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, and U01CA214125 as U24CA210972 to D.F. L.D. and S.P. and Contract GR0012005 to L.D. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I, Task Order HHSN26100064. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. Study Conception & Design: W.L. R.J.L. R.J. S.F. and L.D.; Performed Experiment or Data Collection: W.L. R.L. I.K. E.D. Y.L. S.S. and M.W.; Computational, Multi-omic, & Statistical Analyses: W.L, R.J.L. E.P. Y.S. A.G. and X.L.; Data Interpretation & Biological Analysis: W.L, R.J.L. R.G.J. S.M.F. E.P. Y.G. R.L. M.W. and H.S.; Writing - Original Drafts: W.L. and R.J.L.; Writing - Review & Editing: W.L. R.J.L. R.J. S.F. E.P. Y.G. M.C.W. Y.S. A.G. X.L. Y.L. D.R.M. K.R. A.L. A.R. and L.D.; Supervision: W.L. and L.D.; Administration:W.L. S.P. D.F. H.R. D.R.M. K.R. A.L. A.R. and L.D. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. During the preparation of this work the author(s) used ChatGPT to enhance its readability. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication. |
| Nota: |
We thank InPrint for the editing, Matthew A. Wyczalkowski for feedback on figures, and BioRender for diagrams. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) is supported by the National Cancer Institute of the National Institutes of Health under award numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, and U01CA214125 as U24CA210972 to D.F., L.D., and S.P., and Contract GR0012005 to L.D. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I, Task Order HHSN26100064. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. |
| Drets: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Llengua: |
Anglès |
| Document: |
Article ; recerca ; Versió publicada |
| Matèria: |
DNA Methylation ;
Endometrial Neoplasms ;
Epigenesis, Genetic ;
Female ;
Gene Expression Regulation, Neoplastic ;
Humans ;
Multiomics |
| Publicat a: |
Cancer Cell, Vol. 41 Núm. 9 (november 2023) , p. 1567-1585.e7, ISSN 1878-3686 |
visitant ::
identificació
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
