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  3. Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations

Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations

  • Genome Biol. 2025 May 9;26(1):124. doi: 10.1186/s13059-025-03596-5.
Sebastian Gregoricchio 1,  Aleksandar Kojic 2,  Marlous Hoogstraat 2 3,  Karianne Schuurman 2,  Suzan Stelloo 4,  Tesa M Severson 2 3,  Tracy A O'Mara 5,  Marjolein Droog 2,  Abhishek A Singh 2,  Dylan M Glubb 5,  Lodewyk F A Wessels 3,  Michiel Vermeulen 4 6,  Flora E van Leeuwen 7,  Wilbert Zwart 8 9
Affiliations

Affiliations

  • 1 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.gregoricchio@nki.nl.
  • 2 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 3 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 4 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Geert Grooteplein Zuid 28, 6525GA, Nijmegen, The Netherlands.
  • 5 Cancer Research Program, QIMR Berghofer Medical Research Institute, Locked Bag 2000, Brisbane, QLD, 4029, Australia.
  • 6 Division of Molecular Genetics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 7 Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 8 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. w.zwart@nki.nl.
  • 9 Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands. w.zwart@nki.nl.
PMID: 40346709 DOI: 10.1186/s13059-025-03596-5
Abstract

Background: The incidence and mortality of endometrial Cancer (EC) is on the rise. Eighty-five percent of ECs depend on Estrogen receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors.

Results: We generate epigenomics, transcriptomics, and Hi-C datastreams in healthy and tumor endometrial tissues, identifying robust ERα reprogramming and profound alterations in 3D genome organization that lead to a gain of tumor-specific enhancer activity during EC development. Integration with endometrial Cancer risk single-nucleotide polymorphisms and whole-genome Sequencing data from primary tumors and metastatic samples reveals a striking enrichment of risk variants and non-coding somatic mutations at tumor-enriched ERα sites. Through machine learning-based predictions and interaction proteomics analyses, we identify an enhancer mutation which alters 3D genome conformation, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression of ESR1 in EC.

Conclusions: In summary, we identify a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα.

Keywords

3D genome organization; Endometrial cancer; Epigenetic plasticity in tumor development; Estrogen receptor; Gene regulation; Non-coding somatic mutations.

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