Delineation of the natural history of Ollier disease and Muffucci syndrome and investigation of their genetic bases

项目摘要/摘要 奥利耶病(OD)和Maffucci综合征(MS)是无法治疗的、特征不佳的新发现的癌症 易感性综合征。它们的遗传基础和途径负责疾病的形成和发展 良性肿瘤和恶性肿瘤尚不清楚。我们的长期目标是确定药物治疗的方法 治疗OD和MS患者的骨畸形和恶变并防治相关的非 与这些疾病相关的癌症的综合征候群。我们在此应用程序中的中心假设是 OD和MS是明显的特征不足的癌症易感性综合征，由多个 扰乱HIF-1途径的基因。我们项目的基本原理是表型特征和 确定OD和MS的遗传原因有可能提供一个强有力的科学框架 从而为这些患者和非综合征患者的癌症治疗提供新的药理学策略 同样的癌症形式，如软骨肉瘤和胶质瘤，也可能发生。中心假说 将通过追求三个具体目标进行测试：1)全面定义患者的表型特征 2)发现OD和MS的致病基因和变异 3)确定OD或MS致病变异体在HIF-1途径中的作用。我们将致力于实现这些目标 旨在使用基因组和功能技术的创新组合，应用于一套独特的深度 表型患者。提出的研究具有重要意义，因为它将：1)定义小说的自然历史 癌症易感综合征；2)建立独特的OD和MS种系和肿瘤样本收集 研究用途；3)确定无法治疗的癌症的遗传基础；4)确定HIF-1的作用 在OD和MS中的途径我们的预期结果是确定导致 良性和恶性肿瘤在OD和MS中的形成并充分阐明其表型特征和自然 这些疾病的病史。我们的成果将产生重要的积极影响，为 开发新的药物治疗方法来治疗这些疾病以及那些 相关的非综合征型癌症，如软骨肉瘤和神经胶质瘤。

PROJECT SUMMARY/ABSTRACT Ollier disease (OD) and Maffucci syndrome (MS) are untreatable, poorly characterized, newly recognized cancer susceptibility syndromes. Their genetic bases and pathways responsible for the formation and progression of benign and malignant tumors are not known. Our long-term goal is to identify pharmacological approaches to treat bone deformities and malignant transformation in patients with OD and MS and to prevent/treat related non- syndromic forms of cancers associated with these conditions. Our central hypothesis in this application is that OD and MS are distinct under-characterized cancer susceptibility syndromes caused by variants in multiple genes that disrupt the HIF-1 pathway. The rationale for our project is that phenotypic characterization and identification of the genetic causes of OD and MS have the potential to offer a strong scientific framework whereby new pharmacological strategies to cancer therapy in these patients and patients with the non-syndromic forms of the same cancers, such as chondrosarcomas and gliomas, can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Comprehensively define the phenotypic features of patients with OD and MS; 2) Discover the causative genes and variants of OD and MS in previously uncharacterized cases; 3) Determine the effect of causative variants of OD or MS in the HIF-1 pathway. We will pursue these aims using an innovative combination of genomic and functional techniques applied to a unique set of deeply phenotyped patients. The proposed research is significant because it will: 1) Define the natural history of novel cancer susceptibility syndromes; 2) Establish a unique OD and MS germline and tumor sample collection for research use; 3) Identify the genetic bases of untreatable cancers, and; 4) Determine the role of the HIF-1 pathway in OD and MS. Our expected outcomes are to define the responsible variants and genes that cause benign and malignant tumor formation in OD and MS and to fully elucidate the phenotypic features and natural history of these disorders. Our results will have an important positive impact providing new opportunities for the development of novel pharmacological therapies to treat patients with these diseases as well as those with related non-syndromic forms of cancers such as of chondrosarcomas and gliomas.