Role of cancer-associated mutations in endometriosis

癌症相关突变在子宫内膜异位症中的作用

• 批准号: 10381500
• 负责人: IE-MING SHIH
• 金额: $ 66.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381500
• 关键词: 3-Dimensional; ARID1A gene; Benign; Bioinformatics; Catalogs; Cells; Choristoma; Classification; Clinical; Data; Development; Diagnosis; Disease; Disease Resistance; Endometrial; Endometriomas; Endometrium; Epigenetic Process; Epithelial; Epithelial Cells; Excision; Exhibits; Experimental Models; FDA approved; Fresh Tissue; Functional disorder; Gene Mutation; Genes; Genetic; Genomics; Genotype; Gland; Growth and Development function; Human; Immunohistochemistry; Impairment; Implant; Inflammation; Intestines; KRAS2 gene; Lasers; Lesion; Malignant Neoplasms; Medical; Menstruation; Methylation; Modeling; Molecular; Molecular Disease; Molecular Genetics; Mutation; Normal tissue morphology; Oncogenes; PIK3CA gene; Pain; Pathogenesis; Pathology; Patients; Pelvis; Pharmacology; Phenotype; Pilot Projects; Play; Progesterone; Progestins; Property; Prospective Studies; Prospective cohort; Reproductive Biology; Research; Research Personnel; Resistance; Role; Sampling; Severities; Severity of illness; Signal Transduction; Somatic Mutation; Specimen; Testing; Time; Tissues; Uterus; Variant; Woman; base; cancer surgery; cell growth; clinical phenotype; cohort; diagnostic biomarker; digital; disease classification; disease phenotype; driver mutation; endometriosis; eutopic endometrium; exome; exome sequencing; hormone therapy; improved; in vitro Assay; inhibitor; laser capture microdissection; molecular modeling; mouse model; novel; personalized medicine; precision medicine; predictive marker; response; targeted sequencing

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.

美国数百万妇女患有子宫内膜异位症，这是一种知之甚少的疾病， 由于存在由子宫内膜腺体和位于子宫内膜外的间质组成的病变， 子宫对于对激素治疗无反应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，需要部分肠切除， 盆腔组织摘除术以孕酮为基础的治疗已成为 治疗子宫内膜异位症，但40%的患者出现对孕酮的耐药性。目前 疾病表型的分子机制仍不清楚， 迫切需要预测标记物。越来越多的证据表明， 子宫内膜异位症的发生发展中起着至关重要的作用，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，我们对肿瘤病变的初步研究 显示26%的病变带有体细胞癌相关突变（获得性突变 在流氓细胞中）在被称为癌症“驱动器”的基因中。值得注意的是，含有“驱动器”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兴奋的结果提出了一个新的研究方向，以了解 子宫内膜异位症的发病机制;特别是，生物学信息，分子疾病 分类，以提高诊断和管理。现在需要的是一个全面的 子宫内膜异位症病变体细胞变异的分类及其分子变异的相关性 疾病表型。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主要研究人员，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 捕获显微切割研究300个现有的子宫内膜异位症标本， 癌症相关基因然后，我们将在100名女性的前瞻性研究中验证这些发现 子宫内膜异位症患者和35名对照组。最后，我们将严格测试这些癌症- 使用三种实验模型研究驱动突变促进子宫内膜异位症病变发展 用于子宫内膜异位症研究。预期的结果将加强我们对 子宫内膜异位症的病理生理学和胆固醇耐药机制。研究 将建立子宫内膜异位症的生物学信息分子分类，并代表 子宫内膜异位症的治疗方法