Tatsuya Kobayashi

Uterine fibroids (UFs), the most common tumors in women of reproductive age, are characterized by sex steroid-dependent growth and excessive deposition of extracellular matrix (ECM) surrounding UF smooth muscle cells. Women with symptomatic UFs experience heavy menstrual bleeding and consequent iron-deficiency anemia. They also have a risk of recurrent pregnancy loss, preterm birth, and cesarean delivery, indicating that UFs can negatively affect reproductive outcomes. Various types of immune cells, including innate and adaptive cells, are observed in UFs; however, the impact of these cells on the pathophysiology of UFs remains unclear. Inflammation may play important roles in the growth of UFs, and expression levels of proinflammatory and inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-10, TNF-α, and TGF-β, are upregulated in UFs. These cytokines play important roles in the interaction between growth factors and ECM that is regulated by the sex steroids estrogen and progesterone. Furthermore, proinflammatory mediators are upregulated in females with UFs, with higher expression levels in the endometrium with submucosal and intramural UFs than in the endometrium without UFs, indicating that these proinflammatory cytokines may impair endometrial receptivity, leading to implantation failure in in vitro fertilization programs. Hormonal treatments using gonadotropin releasing hormone analogs and the selective progesterone receptor modulator ulipristal acetate significantly shrink UFs and improve UF-related symptoms. These compounds can regulate local inflammation in UFs and adjacent myometrium. Controlling and improving local inflammation caused by UFs may represent a novel therapeutic strategy for UFs and potentially improve reproductive outcomes in women with symptomatic UFs.

Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroids dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary UFs and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

背景:デュシェンヌ/ベッカー型筋ジストロフィー(DMD/BMD)はともにX染色体上のジストロフィン遺伝子変異を原因とする遺伝性疾患だが,DMDはフレームシフト/ナンセンス変異により若年発症し進行が速い。出生前/着床前診断の対象となりうるためBMDとの鑑別は重要である。症例:11歳女児,ジストロフィン遺伝子のサザンブロット解析でin-frame欠失を認め,BMD保因者であることが示唆された。29歳時,挙児希望にて周産期遺伝カウンセリング目的に来院。MLPA再解析でout-of-frame欠失を認め,DMD保因者であることが示唆された。考察:遺伝子解析方法により欠失領域の判定が異なる結果となった症例を経験した。解析方法の進歩によって,過去の検査結果や解釈が変化することがある。結論:欠失領域の判定は筋ジストロフィーのタイプに直接関係する。周産期遺伝カウンセリングにおいては注意が必要である。(著者抄録)