Authors
Sribalasubashini Muralimanoharan, Ana Corachán, Azad Khosh, Sierra Hathaway, Natalia Garcia, Susivarshini Karthigayan, Claire Schenken, Nicholas Stansbury, Robert Schenken, Maria Victoria Bariani, Qiwei Yang, Eloise Dray, Mazhar Adli, Hortensia Ferrero, Ayman Al-Hendy, Thomas G Boyer
Published in
Scientific reports. Jul 06, 2026. Epub Jul 06, 2026.
Abstract
Uterine fibroids (UFs) are the most important benign neoplastic threat to women's health worldwide, with no long-term noninvasive treatment options currently available. Among known UF driver alterations, somatic mutations in Mediator subunit MED12 are by the far the most prevalent, accounting for up to 80% of these clinically significant lesions. Although it is presently unclear how MED12 mutations trigger neoplastic transformation, MED12-mutant UFs are nonetheless characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor development. However, the basis by which MED12 mutations drive genomic instability is not known. Herein, we show that R-loop-driven replication stress in MED12-mutant UFs leads to DNA under-replication and mitotic segregation errors that drive chromosomal instability. Notably, we find that vitamin D3 (VD3), a modifiable risk factor in UF development, suppresses pathogenic R-loop accrual and ameliorates replication stress-driven chromosomal instability, contributing to growth inhibition of patient-derived MED12-mutant UF xenografts in vivo. Altogether these findings uncover a molecular basis by which the predominant UF driver converges with a known risk factor at the interface of genomic instability, with significant translational implications for personalized UF prevention and treatment.
PMID:
42409897
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.
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