American journal of obstetrics and gynecology · 2026
Clinical trajectories and magnetic resonance imaging-based triage of uterine leiomyoma molecular subtypes: a large-scale retrospective analysis of 720 genotyped tumors.
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Liu Xueyan, Ya Fei, Zhao Mengling, Zhang Yong, Yan Shuping, Li Bijun, Si Lulu, Fu Hanlin, Liu Yana, Guo Ruixia
Аннотация
BACKGROUND: Uterine leiomyomas are genetically heterogeneous, yet the clinical and prognostic implications of their primary molecular drivers remain poorly integrated into surgical practice.
OBJECTIVE: This study aims to characterize the clinical phenotypes and pharmacogenomic responses of major molecular subtypes and evaluate the predictive value of T2-weighted magnetic resonance imaging for surgical prognosis.
STUDY DESIGN: We enrolled premenopausal women who underwent myomectomy or hysterectomy at the Department of Gynaecology, the First Affiliated Hospital of Zhengzhou University from January 2019 to June 2025. All leiomyomas were molecularly genotyped as MED12-mutant, HMGA2-overexpressing, fumarate hydratase-deficient, or triple-negative (3X, not belonging to the MED12-mutant, HMGA2-overexpressing, or fumarate hydratase-deficient genotypes). First, clinical and morphological characteristics were compared across the full cohort (n=720). Second, a pharmacogenomic subset of patients receiving preoperative gonadotropin-releasing hormone agonist (n=84) was analyzed for genotype-specific volume reduction. Third, a subset of 502 patients receiving myomectomy and completing a follow-up of more than 12 months was analyzed for genotype-specific reintervention risk. Finally, an imaging "gold standard" consisting of 461 patients with preoperative magnetic resonance imaging and long-term follow-up postmyomectomy was used to assess surgical reintervention rates via Kaplan-Meier estimators.
RESULTS: HMGA2 tumors were most likely to be solitary and submucosal (International Federation of Gynecology and Obstetrics type 0-2), while FH-deficient cases showed the highest rates of multiple tumors (≥5). MED12-mutant tumors demonstrated significantly lower gonadotropin-releasing hormone agonist-induced volume reduction compared to 3X variants (adjusted P value =.027). The FH group exhibited the highest surgical reintervention rate, a trend that was even more pronounced after excluding patients receiving postoperative gonadotropin-releasing hormone agonist. Magnetic resonance imaging analyses revealed that low T2-weighted magnetic resonance imaging signal intensity was highly specific for MED12 mutations, whereas a "mixed high" signal was prognostically indicative for fumarate hydratase deficiency and correlated with a higher surgical reintervention rate.
CONCLUSION: Molecular subtypes of uterine leiomyomas dictate distinct clinical behaviors. MED12 mutations predict hormonal therapy resistance, while FH deficiency signals aggressive recurrence. A T2-weighted magnetic resonance imaging-based classification system showed some phenotype-genotype relationships, although these findings require validation in independent cohorts.
OBJECTIVE: This study aims to characterize the clinical phenotypes and pharmacogenomic responses of major molecular subtypes and evaluate the predictive value of T2-weighted magnetic resonance imaging for surgical prognosis.
STUDY DESIGN: We enrolled premenopausal women who underwent myomectomy or hysterectomy at the Department of Gynaecology, the First Affiliated Hospital of Zhengzhou University from January 2019 to June 2025. All leiomyomas were molecularly genotyped as MED12-mutant, HMGA2-overexpressing, fumarate hydratase-deficient, or triple-negative (3X, not belonging to the MED12-mutant, HMGA2-overexpressing, or fumarate hydratase-deficient genotypes). First, clinical and morphological characteristics were compared across the full cohort (n=720). Second, a pharmacogenomic subset of patients receiving preoperative gonadotropin-releasing hormone agonist (n=84) was analyzed for genotype-specific volume reduction. Third, a subset of 502 patients receiving myomectomy and completing a follow-up of more than 12 months was analyzed for genotype-specific reintervention risk. Finally, an imaging "gold standard" consisting of 461 patients with preoperative magnetic resonance imaging and long-term follow-up postmyomectomy was used to assess surgical reintervention rates via Kaplan-Meier estimators.
RESULTS: HMGA2 tumors were most likely to be solitary and submucosal (International Federation of Gynecology and Obstetrics type 0-2), while FH-deficient cases showed the highest rates of multiple tumors (≥5). MED12-mutant tumors demonstrated significantly lower gonadotropin-releasing hormone agonist-induced volume reduction compared to 3X variants (adjusted P value =.027). The FH group exhibited the highest surgical reintervention rate, a trend that was even more pronounced after excluding patients receiving postoperative gonadotropin-releasing hormone agonist. Magnetic resonance imaging analyses revealed that low T2-weighted magnetic resonance imaging signal intensity was highly specific for MED12 mutations, whereas a "mixed high" signal was prognostically indicative for fumarate hydratase deficiency and correlated with a higher surgical reintervention rate.
CONCLUSION: Molecular subtypes of uterine leiomyomas dictate distinct clinical behaviors. MED12 mutations predict hormonal therapy resistance, while FH deficiency signals aggressive recurrence. A T2-weighted magnetic resonance imaging-based classification system showed some phenotype-genotype relationships, although these findings require validation in independent cohorts.