Role of cancer-associated mutations in endometriosis

在美国，数百万女性患有子宫内膜异位症，这是一种鲜为人知的疾病 由子宫内膜腺和间质组成的病变位于子宫内膜外 子宫。对于激素治疗无效的深度侵袭性子宫内膜异位症患者， 手术切除可以像癌症手术一样广泛，需要节段性肠段切除和 切除盆腔组织的手术。以黄体酮为基础的治疗已成为 治疗子宫内膜异位症，但40%的患者出现黄体酮耐药。目前， 该病表型的分子机制尚不清楚，诊断和治疗 迫切需要预测性标记物。有越来越多的证据表明基因 贡献在子宫内膜异位症的发展中起着关键作用，并可能解释不同的 子宫内膜异位症的类型和严重程度。重要的是，我们对子宫内膜异位症病变的初步研究 显示26%的病变含有与癌症相关的体细胞突变(获得性突变 在被称为癌症“驱动因素”的基因中)。值得注意的是，含有“司机”的病变 突变与深度侵袭性子宫内膜异位症有关，这是一种特别痛苦和致残的疾病 子宫内膜异位症。这些令人振奋的结果表明了一个新的研究方向来理解 子宫内膜异位症的发病机制；具体地说，是一种生物知情的分子疾病 分类施策，提高诊疗水平。现在需要的是一个全面的 子宫内膜异位症病变的体细胞变异类型及其与分子改变的相关性 有疾病表型的。基于这些结果，我们建议建立一个分子 子宫内膜异位症的分类与疾病的临床表型相关。本研究 包括具有独特和互补专业知识的关键调查人员，包括生殖 生物学、分子遗传学和基因组学、病理学和生物信息学。首先，我们将使用激光 捕捉显微解剖以研究300例现有的子宫内膜异位症标本中这些变化 癌症相关基因。然后，我们将在一项针对100名女性的前瞻性研究中验证这一发现 子宫内膜异位症组35例，对照组35例。最后，我们将严格测试这些癌症-- 用三种实验模型研究驱动基因突变促进子宫内膜异位症病变的发展 用于子宫内膜异位症的研究。预期的结果将增进我们对 子宫内膜异位症的病理生理及孕激素抵抗机制。这些研究 将建立一个基于生物信息的子宫内膜异位症分子分类，并代表 子宫内膜异位症个体化医疗的第一步。

Millions of women in the US suffer from endometriosis, a poorly understood disease characterized by the presence of lesions composed of endometrial glands and stroma located outside the uterus. For women with deeply invasive endometriosis that does not respond to hormonal therapy, surgical removal can be as extensive as cancer surgery, requiring segmental bowel excision and extirpative resection of pelvic tissues. Progesterone-based therapy has become the mainstay in treating endometriosis, but progesterone-resistance occurs in 40% of patients. Currently, the molecular mechanisms underlying the disease phenotypes remain unclear and diagnostic and predictive markers are urgently needed. There is a growing body of evidence that genetic contributions play a pivotal role in the development of endometriosis and may explain the different types and severity of endometriosis. Importantly, our preliminary studies of endometriotic lesions showed that 26% of lesions harbored somatic, cancer-associated mutations (acquired mutations in rogue cells) in genes known as “drivers” of cancer. Notably, the lesions containing the “driver” mutations were associated with deeply invasive endometriosis, a particularly painful and disabling form of endometriosis. These exciting results suggest a new research direction to understand the pathogenesis of endometriosis; specifically, a biologically informed, molecular disease classification to improve diagnosis and management. What is now needed is a comprehensive catalogue of somatic variants of endometriosis lesions and correlation of molecular alterations with disease phenotypes. Based on these results, we propose to establish a molecular classification of endometriosis correlated with the clinical phenotype of disease. This study includes key investigators with unique and complementary expertise including reproductive biology, molecular genetics and genomics, pathology, and bioinformatics. First, we will use laser capture microdissection to study 300 existing endometriosis specimens for changes in these cancer-associated genes. Then, we will validate the findings in a prospective study of 100 women with endometriosis, and 35 control subjects. Finally, we will rigorously test how these cancer- driver mutations promote lesion development in endometriosis using three experimental models used in endometriosis research. The expected results will enhance our understanding of the pathophysiology of endometriosis and the mechanism of progesterone-resistance. The studies will establish a biologically informed molecular classification of endometriosis and represent the first step toward personalized medical treatment of endometriosis.