Ryoko Asano

Impact of MED12 mutation and CDK8 activity on uterine leiomyoma growth and response to gonadotropin-releasing hormone agonist treatment

MED12 exon 2 mutation is the most frequent mutation associated with uterine leiomyomas. MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth. MED12 forms a complex with CDK8 and is involved in the phosphorylation of RNA polymerase II, playing a role in transcriptional regulation. However, its mechanism of action in leiomyoma growth is not clear. We aimed to clarify the relationship between MED12 mutation status, response to gonadotropin-releasing hormone (GnRH) agonist treatment, and CDK8 activity in leiomyomas. We also examined the effects of CDK8 inhibitors on primary cultured uterine leiomyoma cells. We classified 44 surgically removed uterine leiomyomas into four groups according to GnRH agonist use and MED12 mutation status. CDK8 was co-immunoprecipitated from leiomyoma tissue extracts using MED12 antibody to test its kinase activity in vitro , and the amount of phosphorylated substrate was measured. Cell proliferation and apoptosis of primary cultured MED12 wild-type leiomyoma cells were evaluated in the presence of a CDK8 inhibitor and sex steroid hormones. Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomas and 15 leiomyomas with MED12 mutations without GnRH agonist treatment. Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis. MED12 wild-type leiomyoma cells without GnRH agonist treatment showed high CDK8 activity, and inhibition of CDK8 activity suppressed cell growth in vitro .

Novel Subtype Classification of Diffuse Uterine Leiomyomatosis Based on a Nationwide Survey in Japan

ABSTRACT Aim Diffuse uterine leiomyomatosis (DUL) is characterized by numerous uterine leiomyomas within and diffusely replacing the myometrium. However, because of its rarity, the prevalence, diagnostic criteria, and standard treatment for patients with DUL who wish to preserve their fertility remain unknown. This study aimed to clarify the current status of the diagnosis of DUL in Japan. Methods We conducted a web‐based survey targeting 1080 Obstetrics and Gynecology training institutions registered with the Japanese Medical Specialty Board. We asked them whether they had treated patients with DUL over the past 10 years (2013–2022). We obtained magnetic resonance imaging (MRI) scans from institutions that reported clinical experience with DUL, and conducted a central review to determine whether each case was consistent with DUL. We also investigated whether DUL could be classified into subtypes. Results Responses were obtained from 428 institutions, of which 128 reported clinical experience with DUL or DUL‐like multiple uterine leiomyomas, totaling 653 cases. MRI scans from 408 cases were centrally reviewed by a subcommittee, and 307 cases were confirmed as DUL. Based on the imaging characteristics, DUL was classified into three subtypes: total replacement, myometrial replacement, and submucosal‐dominant. Conclusions This survey revealed that 653 cases of DUL or DUL‐like multiple uterine leiomyomas were managed over a 10‐year period in Japan. Based on a central review of MRI scans, DUL can be classified into three distinct subtypes. Given the differences between these subtypes, treatment approaches for patients wishing to preserve fertility may vary, highlighting the need for further investigation.