BACKGROUND Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging uterine disorders in terms of diagnosis and management. Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility. The relative contributions of abnormal endometrial tissue and myometrial smooth muscle cells to the development and growth of adenomyosis are not well understood. Moreover, there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium. OBJECTIVE AND RATIONALE A recent series of next-generation sequencing (NGS) studies have provided the best scientific evidence thus far regarding the cellular origins of adenomyosis and the contributions of new signaling pathways to its pathogenesis, survival, and growth. These seminal studies on endometrium, adenomyosis and endometriosis demonstrate or support the following key points. (i) Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis. Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis. (ii) KRAS and other less frequent mutations are limited to endometrial-type epithelial cells. They are also observed in endometriosis, indicating that the disease process in adenomyosis is similar to that in endometriosis and distinct from that of uterine fibroids. (iii) Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis. Together, these findings suggest that distinct cell populations in eutopic endometrial tissue play key roles in the etiology of adenomyosis. Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis. In this context, common patterns of aberrant gene expression have been reported both in adenomyosis and endometriosis. These include pathways that favor increased estrogen biosynthesis, decreased estradiol metabolism, a unique estrogen receptor beta (ESR2)-driven inflammatory process, and progesterone resistance due to decreased progesterone receptor expression. Since adenomyosis exhibits a uniquely estrogen-driven inflammatory process and progesterone resistance, we discuss the interactions between these molecular characteristics and signaling pathways induced by the newly discovered KRAS mutations. SEARCH METHODS We conducted a comprehensive search using PubMed for human and animal studies published until 2020 in the following areas: adenomyosis, endometriosis, endometrium, NGS, whole-exome sequencing, whole-genome sequencing, RNA sequencing, targeted deep sequencing, epigenetics, driver mutation, KRAS, progesterone resistance, estrogen action and steroid production. OUTCOMES Targeted deep sequencing analyses of epithelial cells in adenomyosis and adjacent basalis endometrial glands demonstrated recurring KRAS mutations in both cell types. This finding suggests that adenomyosis originates from basalis endometrium. Epithelial cells of the endometrium, adjacent adenomyosis and co-occurring endometriosis also share identical KRAS mutations. These findings suggest both adenomyosis and endometriosis are oligoclonal tissues that arise from endometrial cell populations carrying a specific driver mutation that most commonly affects the KRAS gene. WIDER IMPLICATIONS Adenomyosis usually follows an event such as pregnancy that has disrupted the integrity of the endometrial–myometrial junction followed by repetitious menstrual episodes that increase the likelihood of the entrapment of the basalis endometrium within the myometrium. Glandular epithelial cells carrying KRAS mutations and located within the deep crypts of basalis endometrium may become entrapped and invade myometrial tissue to give rise to adenomyosis. Evidence suggests that KRAS mutations may be responsible, in part, for previously observed phenomena such as prolonged cell survival and progesterone resistance in adenomyosis.

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子宫腺肌病发病机制：来自下一代测序的见解

背景技术子宫腺肌病的特征是在子宫肌层中存在被肥大平滑肌细胞包围的子宫内膜组织岛，是诊断和治疗方面最具挑战性的子宫疾病之一。子宫腺肌症表现为盆腔疼痛、子宫出血过多、贫血和不育。异常子宫内膜组织和肌层平滑肌细胞对子宫腺肌症的发展和生长的相对贡献尚不清楚。此外，关于子宫腺肌病的起源的争论仍在继续。两种相互竞争的理论描述了基底子宫内膜内陷到子宫肌层或子宫内膜内残余子宫内膜干/祖细胞的化生分化。目标和理由 最近的一系列下一代测序 (NGS) 研究提供了迄今为止关于子宫腺肌病的细胞起源以及新的信号通路对其发病机制、存活和生长的贡献的最佳科学证据。这些关于子宫内膜、子宫腺肌病和子宫内膜异位症的开创性研究证明或支持以下关键点。(i) KRAS 的突变映射到腔内子宫内膜组织和位于近端的子宫腺肌组织样本，支持发病机制的内陷理论。在子宫肌瘤的平滑肌细胞中发现的驱动突变在子宫腺肌病中不存在。(ii) KRAS 和其他不太常见的突变仅限于子宫内膜型上皮细胞。它们也在子宫内膜异位症中观察到，说明子宫腺肌病的病程与子宫内膜异位症相似，与子宫肌瘤不同。(iii) KRAS 的激活突变刺激特定途径以增加细胞存活和增殖，并与子宫腺肌症中的孕酮抵抗有关。总之，这些发现表明在位子宫内膜组织中不同的细胞群在子宫腺肌病的病因学中起关键作用。疾病严重程度对卵巢类固醇和排卵周期的依赖是子宫腺肌病的一个独特特征。在这种情况下，在子宫腺肌病和子宫内膜异位症中都报道了常见的异常基因表达模式。这些包括有利于增加雌激素生物合成、减少雌二醇代谢、独特的雌激素受体 β (ESR2) 驱动的炎症过程的途径，黄体酮受体表达减少导致的黄体酮抵抗。由于子宫腺肌病表现出独特的雌激素驱动的炎症过程和孕激素抵抗，我们讨论了这些分子特征与新发现的 KRAS 突变诱导的信号通路之间的相互作用。搜索方法 我们使用 PubMed 对截至 2020 年在以下领域发表的人类和动物研究进行了全面搜索：子宫腺肌病、子宫内膜异位症、子宫内膜、NGS、全外显子组测序、全基因组测序、RNA 测序、靶向深度测序、表观遗传学、驱动程序突变、KRAS、孕激素抵抗、雌激素作用和类固醇产生。结果 对子宫腺肌病和邻近基底膜子宫内膜腺体上皮细胞的靶向深度测序分析表明，这两种细胞类型中都存在反复的 KRAS 突变。这一发现表明子宫腺肌病起源于基底子宫内膜。子宫内膜的上皮细胞、邻近的子宫腺肌病和同时发生的子宫内膜异位症也具有相同的 KRAS 突变。这些研究结果表明，子宫腺肌病和子宫内膜异位症都是由子宫内膜细胞群产生的寡克隆组织，这些细胞群携带最常影响 KRAS 基因的特定驱动突变。更广泛的影响 子宫腺肌病通常发生在诸如妊娠破坏了子宫内膜-肌层交界处完整性的事件之后，然后是重复的月经发作，这增加了基底层子宫内膜卡在子宫肌层内的可能性。携带 KRAS 突变并位于基底层子宫内膜深部隐窝内的腺上皮细胞可能被困住并侵入子宫肌层组织导致子宫腺肌病。有证据表明，KRAS 突变可能部分导致先前观察到的现象，例如子宫腺肌病中的细胞存活时间延长和孕激素抵抗。