Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is a syndrome that predisposes individuals to the development of one or more benign or malignant parathyroid tumors, ossifying fibromas of the mandible and/or maxilla, benign or malignant uterine tumors and, less commonly, cystic kidney lesions, renal hamartomas or Wilm's tumors. Affected individuals may develop multiple primary parathyroid, jaw, uterine and/or kidney tumors over the course of their lifetime. Inactivating mutations of theHRPT2 tumor suppressor gene (also called CDC73), encoding parafibromin, were identified as the genetic cause of HPT-JT in the majority of affected kindreds. Subsequently, screens of sporadic parathyroid carcinomas, ossifying fibromas of the mandible and renal tumors revealed both germline and somatic mutations of HRPT2. The proposed studies are designed to address the mechanisms through which loss of Hrpt2/parafibromin promotes neoplasia in the parathyroid glands and jaws, in the pathophysiologically relevant experimental context of an intact animal. To study the pathophysiological consequences of knockout of Hrpt2 in vitro, genetically- engineered mice in which the Hrpt2 gene is flanked by two loxP sites have been generated and will be crossed with two different transgenic mouse strains, PTH-Cre and Wnt1-Cre. These crosses will result in offspring with Hrpt2 deletion in the parathyroid glands or mandible, respectively. Development of these two mouse models will provide a means for dissecting the molecular basis of HPT-JT, sporadic parathyroid tumors and ossifying jaw fibromas and may ultimately enable the development of new diagnostic and treatment strategies.

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This research will examine important molecular mechanisms causing hyperparathyroidism, a common human endocrine disorder, and ossifying fibroma, a type of non-cancerous bone tumor, through the study of the Hrpt2 gene. Individuals with an abnormal copy of HRPT2 may develop one or more cancerous or non-cancerous tumors in the parathyroid glands, jaws, uterus and/or kidneys over the course of their lifetime. This research will help us to understand how changes in the HRPT2 gene cause cancer, will allow for insight into the progression from a benign (non-cancerous) tumor to a malignant cancer, capable of spreading into other parts of the body, and also to test cancer-preventative strategies and treatment interventions that may ultimately be beneficial to human patients suffering from a wide variety of cancer types.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Postdoctoral Individual National Research Service Award (F32)
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NIDCR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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University of Connecticut
Other Basic Sciences
Schools of Medicine
United States
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Costa-Guda, Jessica; Arnold, Andrew (2014) Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors. Mol Cell Endocrinol 386:46-54
Costa-Guda, Jessica; Soong, Chen-Pang; Parekh, Vaishali I et al. (2013) Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas. Horm Cancer 4:301-7
Costa-Guda, Jessica; Marinoni, Ilaria; Molatore, Sara et al. (2011) Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab 96:E701-6