Multiomic analysis of uterine leiomyomas in self-described Black and White women: molecular insights into health disparities - 30/05/24

Doi : 10.1016/j.ajog.2024.04.051

Nicholas W. Bateman, PhD ^a,^b,^c, Tamara Abulez, MS ^a,^c, Christopher M. Tarney, MD ^a,^b, Maria V. Bariani, PhD ^d, Jordan A. Driscoll, MS ^a,^c, Anthony R. Soltis, PhD ^d, Ming Zhou, PhD ^e, Brian L. Hood, PhD ^a,^c, Tracy Litzi, BS ^a,^c, Kelly A. Conrads, PhD ^a,^c, Amanda Jackson, MD ^a, Julie Oliver, MS ^a,^c, Satishkumar Ranganathan Ganakammal, PhD ^f, Frank Schneider, MD ^g, Clifton L. Dalgard, PhD ^e, Matthew D. Wilkerson, PhD ^e, Barbara Smith, MSc ^h, Victor Borda, PhD ⁱ, Timothy O’Connor, PhD ⁱ, James Segars, MD ^h, S. Abbas Shobeiri, MD ^f, Neil T. Phippen, MD ^a,^b, Kathleen M. Darcy, PhD ^a,^b,^c, Ayman Al-Hendy, MD, PhD ^d, Thomas P. Conrads, PhD ^a,^b,^f,^⁎ , George Larry Maxwell, MD ^a,^b,^f,^⁎
^a 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
^b Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD
^c The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc, Bethesda, MD
^d The University of Chicago College of Medicine, Chicago, IL
^e The American Genome Center, Center for Military Precision Health, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD
^f Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA
^g Emory University School of Medicine, Atlanta, GA
^h Johns Hopkins University Medical Center, Baltimore, MD
ⁱ Program in Personalize and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD

^∗Corresponding author: Thomas P. Conrads, PhD.^∗George Larry Maxwell, MD.

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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.

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Key words : MED12, multiomics, racial disparities, uterine fibroids, uterine leiomyoma

Plan

	N.W.B., T.A., and C.M.T. contributed equally to this work.
	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.
	Data generated in this study (ie, RNA sequencing and proteomic data) will be accessible via the Mendeley Data Commons here: j9384ncmks?a=9571bbce-a5de-4f72-92fe-6564dd021a49 and ProteomeXChange under study accessions no. PXD029323. Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact G.L.M. (George.Maxwell@inova.org).
	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.
	The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University of the Health Sciences, Department of the Navy, Department of the Air Force, Department of the Army, Department of Defense, or the United States Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the United States Government. The author(s) are military service members. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
	Cite this article as: Bateman NW, Abulez T, Tarney CM, et al. Multiomic analysis of uterine leiomyomas in self-described Black and White women: molecular insights into health disparities. Am J Obstet Gynecol 2024;XXX:XX–XX.