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Background <p>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.</p> Results <p>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 <i>ESR1</i> in EC.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月9日

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  • Sebastian Gregoricchio,
  • Aleksandar Kojic,
  • Marlous Hoogstraat,
  • Karianne Schuurman,
  • Suzan Stelloo,
  • Tesa M. Severson,
  • Tracy A. O’Mara,
  • Marjolein Droog,
  • Abhishek A. Singh,
  • Dylan M. Glubb,
  • Lodewyk F. A. Wessels,
  • Michiel Vermeulen,
  • Flora E. van Leeuwen,
  • Wilbert Zwart

摘要

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.