Abstract
Background: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients. Objective: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women. Study Design: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses. Results: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38. Conclusion: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations.
Original language | English (US) |
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Pages (from-to) | 321.e1-321.e11 |
Journal | American journal of obstetrics and gynecology |
Volume | 231 |
Issue number | 3 |
DOIs | |
State | Published - Sep 2024 |
Funding
This work was funded by awards HU0001-16-2-0006, HU0001-19-2-0031, HU0001-20-2-0033, and HU0001-21-2-0027, and HU0001-22-2-0016 from the Uniformed Services University of the Health Sciences from the Defense Health Program to the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc in support of the Gynecologic Cancer Center of Excellence Program. T.P.C. is a ThermoFisher Scientific, Inc Scientific Advisory Board member and receives research funding from AbbVie. G.L.M. is a consultant for Kiyatec, GSK, and Merck. All of these activities are unrelated to this study. Thanks and appreciation are extended to the patients and family members who participated in the Tissue and Data Acquisition Study of Gynecologic Disease protocol and the staff from Regulatory Affairs, Clinical Data Management and Coordination, Procurement, Processing, and Biobanking at the Inova Health System. The authors would like to acknowledge the contributions of Uma Rao, MD, who sadly passed away during the finalization of this work.
Keywords
- MED12
- multiomics
- racial disparities
- uterine fibroids
- uterine leiomyoma
ASJC Scopus subject areas
- Obstetrics and Gynecology