Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai 200011, China.
Hum Reprod Update. 2020 Apr 15;26(3):423-449. doi: 10.1093/humupd/dmz047.
Endometriosis is a benign gynaecological disease. Thus, it came as a complete surprise when it was reported recently that the majority of deep endometriosis lesions harbour somatic mutations and a sizeable portion of them contain known cancer-associated mutations (CAMs). Four more studies have since been published, all demonstrating the existence of CAMs in different subtypes of endometriosis. While the field is still evolving, the confirmation of CAMs has raised many questions that were previously overlooked.
A comprehensive overview of CAMs in endometriosis has been produced. In addition, with the recently emerged understanding of the natural history of endometriotic lesions as well as CAMs in normal and apparently healthy tissues, this review attempts to address the following questions: Why has there been such a wild discrepancy in reported mutation frequencies? Why does ectopic endometrium have a higher mutation rate than that of eutopic endometrium? Would the presence of CAMs in endometriotic lesions increase the risk of cancer to the bearers? Why do endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart? What clinical implications, if any, do the CAMs have for the bearers? Do these CAMs tell us anything about the pathogenesis and/or pathophysiology of endometriosis?
The PubMed database was searched, from its inception to September 2019, for all papers in English using the term 'endometriosis and CAM', 'endometriosis and cancer-driver mutation', 'somatic mutations', 'fibrosis', 'fibrosis and epigenetic', 'CAMs and tumorigenesis', 'somatic mutation and normal tissues', 'oestrogen receptor and fibrosis', 'oxidative stress and fibrosis', 'ARID1A mutation', and 'Kirsten rat sarcoma mutation and therapeutics'. All retrieved papers were read and, when relevant, incorporated into the review results.
Seven papers that identified CAMs in endometriosis using various sequencing methods were retrieved, and their results were somewhat different. Yet, it is apparent that those using microdissection techniques and more accurate sequencing methods found more CAMs, echoing recent discoveries that apparently healthy tissues also harbour CAMs as a result of the replicative aging process. Hence endometriotic lesions, irrespective of subtype, if left intact, would generate CAMs as part of replicative aging, oxidative stress and perhaps other factors yet to be identified and, in some rare cases, develop cancer. The published data still are unable to paint a clear picture on pathogenesis of endometriosis. However, since endometriotic epithelial cells have a higher turnover than their stromal counterpart due to cyclic bleeding, and since the endometriotic stromal component can be formed by refresh influx of mesenchymal cells through epithelial-mesenchymal transition, endothelial-mesenchymal transition, mesothelial-mesenchymal transition and other processes as well as recruitment of bone-marrow-derived stem cells and outflow due to smooth muscle metaplasia, endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart. The epithelial and stromal cellular components develop in a dependent and co-evolving manner. Genes involved in CAMs are likely to be active players in lesional fibrogenesis, and hyperestrogenism and oxidative stress are likely drivers of both CAMs and fibrogenesis. Finally, endometriotic lesions harbouring CAMs would conceivably be more refractory to medical treatment, due, in no small part, to their high fibrotic content and reduced vascularity and cellularity.
The accumulating data on CAMs in endometriosis have shed new light on the pathogenesis and pathophysiology of endometriosis. They also suggest new challenges in management. The distinct yet co-evolving developmental trajectories of endometriotic stroma and epithelium underscore the importance of the lesional microenvironment and ever-changing cellular identity. Mutational profiling of normal endometrium from women of different ages and reproductive history is needed in order to gain a deeper understanding of the pathogenesis. Moreover, one area that has conspicuously received scant attention is the epigenetic landscape of ectopic, eutopic and normal endometrium.
子宫内膜异位症是一种良性妇科疾病。然而，最近有报道称，深部子宫内膜异位症病变中存在体细胞突变，其中相当一部分含有已知的癌症相关突变（CAM），这完全出人意料。此后又有四项研究发表，均证实不同子宫内膜异位症亚型中存在 CAM。尽管该领域仍在不断发展，但 CAM 的确认提出了许多以前被忽视的问题。
本文对子宫内膜异位症中的 CAM 进行了全面概述。此外，随着对子宫内膜异位症病变以及正常和看似健康组织中 CAM 的自然史的最新认识，本综述试图回答以下问题：为什么报告的突变频率存在如此大的差异？为什么异位子宫内膜的突变率高于在位子宫内膜？子宫内膜异位症病变中 CAM 的存在是否会增加携带者患癌症的风险？为什么子宫内膜异位症上皮细胞的突变频率远高于其基质细胞？这些 CAM 对携带者有什么临床意义（如果有的话）？这些 CAM 对子宫内膜异位症的发病机制和/或病理生理学有何启示？
从 PubMed 数据库中检索了自成立以来至 2019 年 9 月发表的所有使用“子宫内膜异位症和 CAM”、“子宫内膜异位症和癌症驱动突变”、“体细胞突变”、“纤维化”、“纤维化和表观遗传学”、“CAM 和肿瘤发生”、“体细胞突变和正常组织”、“雌激素受体和纤维化”、“氧化应激和纤维化”、“ARID1A 突变”和“Kirsten 大鼠肉瘤突变和治疗”等术语的英文文献。阅读所有检索到的文献，并在相关情况下将其纳入综述结果。
检索到 7 篇使用各种测序方法鉴定子宫内膜异位症中 CAM 的论文，其结果有些不同。然而，很明显，那些使用微切割技术和更准确测序方法的论文发现了更多的 CAM，这与最近的发现相呼应，即正常组织也由于复制性衰老过程而存在 CAM。因此，无论亚型如何，如果子宫内膜异位症病变保持完整，它们将作为复制性衰老、氧化应激以及其他尚未确定的因素的一部分产生 CAM，在某些罕见情况下，还会发展为癌症。发表的数据仍然无法清晰描绘子宫内膜异位症的发病机制。然而，由于异位子宫内膜上皮细胞由于周期性出血而具有比基质细胞更高的周转率，并且由于间充质细胞通过上皮-间充质转化、内皮-间充质转化、间皮-间充质转化和其他过程以及招募骨髓源性干细胞以及平滑肌化生引起的外流，子宫内膜异位症的基质成分可以由新流入的间充质细胞形成，因此子宫内膜异位症上皮细胞的突变频率远高于其基质细胞。上皮和基质细胞成分以依赖和共同进化的方式发展。参与 CAM 的基因可能是病变纤维化的活跃参与者，而高雌激素和氧化应激可能是 CAM 和纤维化的驱动因素。最后，由于其富含纤维化、血管生成减少和细胞减少，因此可能会使含有 CAM 的子宫内膜异位症病变更难以治疗。
子宫内膜异位症中 CAM 的累积数据为子宫内膜异位症的发病机制和病理生理学提供了新的认识。它们还提示了管理方面的新挑战。子宫内膜异位症间质和上皮的独特但共同进化的发育轨迹强调了病变微环境和不断变化的细胞身份的重要性。需要对来自不同年龄和生殖史的女性的正常子宫内膜进行突变分析，以深入了解发病机制。此外，一个明显受到关注的领域是异位、在位和正常子宫内膜的表观遗传学景观。
