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; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc, Bethesda, MD.
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; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc, Bethesda, MD.
Am J Obstet Gynecol. 2024 Sep;231(3):321.e1-321.e11. doi: 10.1016/j.ajog.2024.04.051. Epub 2024 May 7.
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.
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.
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.
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.
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.
黑人女性患子宫肌瘤的风险增加，且疾病预后比白人女性差。已经确定了流行病学和分子因素是造成这些差异的原因，但对于从黑人和白人患者中收集的子宫肌瘤进行深入的、多组学分析以研究分子差异的研究仍然很少。
通过对黑人（42 例）和白人（47 例）因症状性子宫肌瘤而行子宫切除术的患者的子宫肌瘤进行多组学分析，确定与患者种族相关的子宫肌瘤组织内的分子改变。
我们对黑人（42 例）和白人（47 例）因症状性子宫肌瘤而行子宫切除术的患者的子宫肌瘤进行了多组学分析。此外，我们还应用正交方法评估了子宫肌瘤的生物力学特性，如二次谐波显微镜、单轴压缩试验和剪切波超声分析。
我们发现黑人女性的 MED12 突变型子宫肌瘤比例更高（增加了>35%；Mann-Whitney U，P<.001）。MED12 突变型肿瘤表现出细胞外基质蛋白的丰度升高，包括几种参与核心基质调节的胶原同工型。使用三色染色和二次谐波显微镜对组织纤维化进行组织学分析证实，MED12 突变型肿瘤比 MED12 野生型肿瘤更纤维化。在一个前瞻性收集的队列中使用剪切波超声检查，即使肌瘤大小相似，黑人患者的肌瘤也比白人患者更硬。此外，这些分析揭示了与非洲和欧洲人群中改变的等位基因频率相关的与 MED12 突变状态无关的、与子宫肌瘤中几种蛋白质的丰度相关的、与种族相关的表达数量性状基因座，包括四肽重复蛋白 38。
我们的研究表明，黑人女性子宫肌瘤中 MED12 突变的发生率更高，与野生型子宫肌瘤相比，这种突变状态与组织纤维化增加相关。我们的研究提供了与子宫肌瘤种族差异相关的分子改变的见解，并提高了我们对这些人群中子宫肌瘤发生的分子病因的理解。
