MED12 mutations in uterine leiomyomas: prediction of volume reduction by gonadotropin-releasing hormone agonists

Abstract

Background: Gonadotropin-releasing hormone agonists are used to treat premenopausal uterine leiomyomas; however, leiomyoma volume reduction is not always achieved. The reduction rate after this treatment varies for each leiomyoma, even in the same patient. Therefore, an effective method for predicting uterine leiomyoma volume reduction is required to reduce the adverse hypoestrogenic effects and drug-related economic burden related to gonadotropin-releasing hormone agonists.

Objective: This study aimed to determine the predictive use of MED12 mutations for evaluating the effect of gonadotropin-releasing hormone agonist treatment concerning reducing uterine leiomyoma volume and to predict the MED12 mutation status based on the findings of magnetic resonance imaging performed before treatment.

Study design: MED12 exon 2 mutation and erythropoietin expression in uterine leiomyomas were evaluated concerning volume reduction, as measured using magnetic resonance imaging. We developed a system for classifying leiomyomas according to T2-weighted magnetic resonance imaging signals to noninvasively predict the presence or absence of MED12 mutations in leiomyomas. Leiomyoma samples (>5 cm) were obtained from 168 patients during surgery (hysterectomy or myomectomy) between 2005 and 2021 at Yokohama City University Hospital. To analyze the rate of leiomyoma volume reduction, 41 patients had been preoperatively administered the gonadotropin-releasing hormone agonist (leuprorelin acetate 3.75 mg, monthly subcutaneous injection) for 3 months; magnetic resonance imaging was performed before and after treatment without contrast material.

Results: Patients with MED12 exon 2 mutations had smaller volume reduction after treatment with the gonadotropin-releasing hormone agonist (P<.001, Mann-Whitney U test) and displayed lower signal intensity on T2-weighted images than those with leiomyomas expressing wild-type MED12 exon 2. The newly proposed magnetic resonance imaging-based classification system showed that MED12 exon 2 mutations were more frequent in the low-signal group than in the high-signal group, with nearly equal proportions of mutated and wild-type MED12 exon 2 leiomyomas noted in the intermediate group. The low-signal group had significantly lower erythropoietin expression levels than the high-signal group (P<.001, Kruskal-Wallis test with the Dunn posthoc analysis).

Conclusion: MED12 mutation status can be a candidate marker for predicting the effect of gonadotropin-releasing hormone agonists on uterine leiomyoma reduction. Magnetic resonance imaging findings can be used to determine MED12 mutation status as a noninvasive strategy to select patients who will most likely benefit from gonadotropin-releasing hormone agonist treatment.

Keywords: erythropoietin; genomics; gonadotropin-releasing hormone analogue; magnetic resonance imaging classification; mediator complex subunit 12; mutation status; predictive marker; uterine fibroid; vessel maturity; volume reduction rate.