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: 9979935
• 负责人: IE-MING SHIH
• 金额: $ 69.82万
• 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/9979935
• 关键词: 3-Dimensional; Benign; Bioinformatics; Biological; Catalogs; Cells; Choristoma; Classification; Clinical; Data; Development; Diagnosis; Disease; Disease Resistance; Endometrial; Endometriomas; Endometrium; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; 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/antagonist; 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.

美国有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