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
  • 1. Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. [email protected].
  • 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. [email protected].
  • 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. [email protected].
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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