Multi-omic Analysis of Uterine Leiomyomas in Self-Described Black and White Women: Molecular Insights into Health Disparities

Nicholas W Bateman; Tamara Abulez; Christopher M Tarney; Maria V Bariani; Jordan A Driscoll; Anthony R Soltis; Ming Zhou; Brian L Hood; Tracy Litzi; Kelly A Conrads; Amanda Jackson; Julie Oliver; Satishkumar Ranganathan Ganakammal; Frank Schneider; Clifton L Dalgard; Matthew D Wilkerson; Barbara Smith; Victor Borda; Timothy O'Connor; James Segars; S Abbas Shobeiri; Neil T Phippen; Kathleen M Darcy; Ayman Al-Hendy; Thomas P Conrads; George Larry Maxwell

doi:10.1016/j.ajog.2024.04.051

Multi-omic Analysis of Uterine Leiomyomas in Self-Described Black and White Women: Molecular Insights into Health Disparities

Am J Obstet Gynecol. 2024 May 7:S0002-9378(24)00577-5. doi: 10.1016/j.ajog.2024.04.051. Online ahead of print.

Authors

Nicholas W Bateman¹, Tamara Abulez², Christopher M Tarney³, Maria V Bariani⁴, Jordan A Driscoll², Anthony R Soltis⁴, Ming Zhou⁵, Brian L Hood², Tracy Litzi², Kelly A Conrads², Amanda Jackson⁶, Julie Oliver², Satishkumar Ranganathan Ganakammal⁷, Frank Schneider⁸, Clifton L Dalgard⁵, Matthew D Wilkerson⁵, Barbara Smith⁹, Victor Borda¹⁰, Timothy O'Connor¹⁰, James Segars⁹, S Abbas Shobeiri⁷, Neil T Phippen³, Kathleen M Darcy¹, Ayman Al-Hendy⁴, Thomas P Conrads¹¹, George Larry Maxwell¹²

Affiliations

¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, Maryland, 20889, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, 20817, USA.
² Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, 20817, USA.
³ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, Maryland, 20889, USA.
⁴ The University of Chicago College of Medicine, Chicago, IL, USA.
⁵ The American Genome Center, Center for Military Precision Health, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20814, USA.
⁶ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA.
⁷ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, Virginia, 22042, USA.
⁸ Emory University School of Medicine, Atlanta, GA, USA.
⁹ Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁰ Program in Personalize and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 USA.
¹¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, Maryland, 20889, USA; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, Virginia, 22042, USA. Electronic address: conrads@whirc.org.
¹² Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, Maryland, 20889, USA; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, Virginia, 22042, USA. Electronic address: george.maxwell@inova.org.

PMID: 38723985
DOI: 10.1016/j.ajog.2024.04.051

Abstract

Background: Black women are at an increased risk to develop uterine leiomyomas (ULMs) and to experience worse disease prognosis compared to White women. Epidemiological and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multi-omic analysis investigating molecular differences in ULMs from Black and White patients.

Objective: To identify molecular alterations within ULM tissues correlating with patient race by multi-omic analyses of ULMs collected from cohorts of Black and White women.

Study design: We performed multi-omic analysis of ULMs from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. Our analysis also included application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, as well as sheer wave ultrasonography analyses.

Results: We found a greater proportion of mediator complex subunit 12 (MED12) mutant ULMs from Black women (>35% increase, Mann Whitney U p = 7E-4). MED12 mutant tumors exhibited elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in regulation of the core matrisome. Histological analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wildtype tumors. Using Sheer Wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer when compared to White patients, even when similar in size. These analyses also uncovered expression quantitative trait loci (eQTL) associated with altered allele frequencies in African and European populations that correlated with differential abundance of several proteins in ULM that are independent of MED12 mutational status, including multiple eQTL mapping to tetratricopeptide repeat protein 38.

Conclusions: Our study shows that Black women have a higher prevalence of ULMs harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis in comparison with wildtype ULMs. Our study provides insights into molecular alterations underlying racial disparities in ULMs and improves our understanding of the molecular etiology underlying ULM development within these populations.

Keywords: Multi-omics; Proteogenomics; Racial Disparities; Uterine Leiomyoma.