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Background <p>Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in <i>MED12</i> and <i>HMGA2</i>, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood.</p> Methods <p>To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients.</p> Results <p>In addition to confirming the presence of <i>MED12</i> mutations, we identify variants in <i>AHR</i> and <i>COL4A6</i>. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of <i>MED12</i>, <i>AHR</i>, and <i>COL4A6</i>, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of <i>MED12</i>-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding.</p> Conclusions <p>This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.</p>

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A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Chen-Yi Wang,
  • Martin Philpott,
  • Darragh P O’Brien,
  • Anne Ndungu,
  • Jessica Malzahn,
  • Marina Maritati,
  • Neelam Mehta,
  • Vicki Gamble,
  • Beatriz Martinez-Burgo,
  • Sarah Bonham,
  • Roman Fischer,
  • Kurtis Garbutt,
  • Christian M. Becker,
  • Sanjiv Manek,
  • Adrian L. Harris,
  • Frank Sacher,
  • Maik Obendorf,
  • Nicole Schmidt,
  • Jörg Müller,
  • Thomas M. Zollner,
  • Krina T. Zondervan,
  • Benedikt M. Kessler,
  • Udo Oppermann,
  • Adam P. Cribbs

摘要

Background

Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood.

Methods

To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients.

Results

In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding.

Conclusions

This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.