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

基本信息

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
项目类别：
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

项目摘要

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.

美国数百万女性患有子宫内膜异位症，这是一种人们知之甚少的疾病，其特征是由位于子宫外的子宫内膜腺体和间质组成的病变的存在对于患有深部浸润性子宫内膜异位症且对激素治疗无反应的女性，手术切除的范围可能与癌症手术一样广泛，需要部分肠切除和基于孕激素的盆腔组织摘除术已成为主要治疗方法。治疗子宫内膜异位症，但目前 40% 的患者出现孕激素抵抗。疾病表型背后的分子机制仍不清楚，诊断和迫切需要预测标记越来越多的证据表明遗传。贡献在子宫内膜异位症的发展中发挥着关键作用，并可能解释不同的原因重要的是，我们对子宫内膜异位病变的初步研究。研究表明，26% 的病变存在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，病变包含“驱动因素”。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这些令人兴奋的结果提出了了解子宫内膜异位症的新研究方向。子宫内膜异位症的发病机制；特别是一种生物学分子疾病；现在需要的是全面的分类以改进诊断和管理。子宫内膜异位症病变的体细胞变异目录和分子改变的相关性基于这些结果，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。包括具有独特和互补专业知识（包括生殖）的关键研究人员生物学、分子遗传学和基因组学、病理学和生物信息学。捕获显微解剖来研究 300 个现有子宫内膜异位症标本的变化然后，我们将在对 100 名女性进行的前瞻性研究中验证这些结果。最后，我们将严格测试这些癌症如何- 使用三种实验模型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的预期结果将增强我们对子宫内膜异位症的理解。子宫内膜异位症的病理生理学和孕激素抵抗机制。将建立子宫内膜异位症的生物学分子分类并代表子宫内膜异位症个性化医疗的第一步。