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Cited by 105Epigenetics and DNA MethylationCancer Genomics and DiagnosticsChromatin Remodeling and Cancer

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

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Liang, Wen-Wei, Lu, Rita Jui-Hsien, Jayasinghe, Reyka G., Foltz, Steven M., Porta-Pardo, Eduard, Geffen, Yifat, Wendl, Michael C., Lazcano, Rossana +124 more·2023·Cancer Cell
DOI 10.1016/j.ccell.2023.07.013PMC PMC11613269
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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.

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  • Alterations of methylation patterns are associated with disease development and allow to distinguish healthy from diseased states, including cancer.

    “Importantly, alterations of methylation patterns are associated with disease development and allow to distinguish healthy from diseased states, including cancer [8, 12, 31].”

    From Comprehensive in silico CpG methylation analysis in hepatocellular carcinoma identifies tissue- and tumor-type specific marks disconnected from gene expression (2024) · cites this paper as [31]

    The Introduction links aberrant DNA methylation to cancer development and progression. The Results (Aberrant methylation associated with therapeutic vulnerabilities) report pronounced methylation differences between tumors and corresponding normal-adjacent tissues. This supports distinguishing cancer tissue from adjacent non-tumor tissue, but does not establish the broader claim for diseases generally or for healthy individuals. (LLM, conf=0.84)

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Authors
Liang, W.-W., Lu, R. J.-H., Jayasinghe, R. G., Foltz, S. M., Porta-Pardo, E., Geffen, Y., Wendl, M. C., Lazcano, R., Kolodziejczak, I., Song, Y., Govindan, A., Demicco, E. G., Li, X., Li, Y., Sethuraman, S., Payne, S. H., Fenyö, D., Rodriguez, H., Wiznerowicz, M., Shen, H., Mani, D. R., Rodland, K. D., Lazar, A. J., Robles, A. I., Ding, L., Aguet, F., Akiyama, Y., An, E., Anand, S., Anurag, M., Babur, O., Bavarva, J., Birger, C., Birrer, M., Calinawan, A., Cantley, L. C., Cao, S., Carr, S., Ceccarelli, M., Chan, D., Chinnaiyan, A., Cho, H., Chowdhury, S., Cieslik, M., Clauser, K., Colaprico, A., Zhou, D. C., da Veiga Leprevost, F., Day, C., Dhanasekaran, M., Domagalski, M., Dou, Y., Druker, B., Edwards, N., Ellis, M., Selvan, M. E., Francis, A., Getz, G., Gillette, M. A., Robles, T. G., Gosline, S., Gümüş, Z., Heiman, D., Hiltke, T., Hong, R., Hostetter, G., Hu, Y., Huang, C., Huntsman, E., Iavarone, A., Jaehnig, E., Jewel, S., Ji, J., Jiang, W., Lee Johnson, J., Katsnelson, L., Ketchum, K., Krug, K., Kumar-Sinha, C., Lei, J., Liao, Y., Lindgren, C., Liu, T., Liu, W., Ma, W., Rodrigues, F. M., McKerrow, W., Mesri, M., Nesvizhskii, A. I., Newton, C., Oldroyd, R., Omenn, G., Paulovich, A., Petralia, F., Pugliese, P., Reva, B., Ruggles, K., Rykunov, D., Satpathy, S., Savage, S., Schadt, E., Schnaubelt, M., Schraink, T., Shi, Z., Smith, D., Song, X., Stathias, V., Storrs, E., Tan, J., Terekhanova, N., Thangudu, R., Thiagarajan, M., Tignor, N., Wang, J., Wang, L.-B., Wang, P., Wang, Y. (., Wen, B., Wu, Y., Yao, L., Yaron, T. M., Yi, X., Zhang, B., Zhang, H., Zhang, Q., Zhang, X., Zhang, Z., Chan, D. W., Dhanasekaran, S. M., Schürer, S., Smith, R. D., & Wyczalkowski, M. A.
Affiliations
  • Washington University in St. Louis (US)
  • Broad Institute (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Mount Sinai Hospital (CA)
  • Brigham Young University (US)
  • NYU Langone Health (US)
  • National Cancer Institute (US)
  • Poznan University of Medical Sciences (PL)
  • Van Andel Institute (US)
  • Pacific Northwest National Laboratory (US)
  • New York University (US)
Corresponding author
Ding, Li
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2023-09
Volume
41
Issue
9
Pages
1567-1585.e7
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2023.07.013
PMC
PMC11613269
OpenAlex
W4385813796
Cited by
105
References
21
Citations by year
2026: 31 · 2025: 38 · 2024: 33 · 2023: 3
FWCI
9.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, other-oa)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (HHSN26100064)
  • U.S. Department of Health and Human Services
  • National Cancer Institute (GR0012005, HHSN261201500003I, U01CA214114, U01CA214116, U01CA214125, U24CA210954, U24CA210955, U24CA210967, U24CA210972, U24CA210979, U24CA210985, U24CA210986, U24CA210993)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
DNA methylation, cell of origin, therapeutic vulnerabilities, STAT5A, FGFR2, endometrial cancer, squamous cell carcinoma, tumor immunosuppression, immune cell depletion, intratumoral heterogeneity, epigenetic regulation, gene expression regulation, multi-omics integration
MeSH terms
Multiomics, Female, Humans, Gene Expression Regulation, Neoplastic, Endometrial Neoplasms, DNA Methylation, Epigenesis, Genetic

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