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Kyle Kurek MD

Development of a Molecular and Genetic Model for Metachondromatosis

Cartilage tumor syndromes are rare skeletal diseases marked by the development of multiple benign cartilaginous bone tumors in childhood, often carrying significant morbidity and risk of developing chondrosarcoma. Tumors can form on the surface of bones, as in the autosomal dominant multiple osteochondroma syndrome (MO), or within the bones, as in the nonhereditary Ollier and Maffucci syndromes. A very rare autosomal dominant syndrome, metachondromatosis (MC), forms both surface and intramedullary tumors. The cartilage tumors in these syndromes develop adjacent to joints and are believed to result from mutations in signaling pathways regulating the growth plate. Only the genetics of MO were previously known, and the cell(s) of origin and mechanism of tumorigenesis for all of these syndromes remains unknown. We have recently identified heterozygous loss-of-function (nonsense, frameshift, splice) mutations of PTPN11 in 10 of 19 families with MC using linkage analysis combined with multiplexed targeted genomic capture and sequencing. PTPN11 encodes SHP2, a protein tyrosine phosphatase important in receptor tyrosine kinase signaling. Preliminary experiments suggest that truncated mutant peptides are not produced, and that loss of the wild-type allele may be required for tumor formation. The proposed research will create a molecular and genetic model for MC, demonstrating the genetic requirements for tumor formation, the molecular signaling events of tumorigenesis, and the cellular source of these tumors. Research will be conducted on tumors excised in MC patients, although the foundation will be the generation of several informative mouse models. Studies of MC will likely yield new understandings of skeletal growth and regulation that will be important for skeletal dysplasia and tumor research. Ultimately, a key signaling pathway may be identified that can be pharmacologically manipulated to biologically control tumors, sparing MC patients recurrent surgeries, disabilities, and the risk of developing chondrosarcomas.

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