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

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.