cyclin-d1 and Hypercalcemia

Topics: Adenocarcinoma; Chromosomes, Human, Pair 11; Cyclin D1; Diagnosis, Differential; Gene Rearrangement; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Parathyroid Hormone; Parathyroid Neoplasms; Parathyroidectomy; Prognosis

Parathyroid carcinoma is an uncommon malignancy. It accounts for less than 1% of cases of primary hyperparathyroidism (HPT). It is manifested by severe hypercalcemia and up to 50% of patients will have concomitant kidney or bone disease. The etiology of parathyroid carcinoma is unknown, however, the recently discovered HRPT2 gene, a tumor suppressor gene encoding for the protein parafibromin, has been implicated in the pathogenesis. Identification of inactivating germ-line mutations in HRPT2 has significant implications for diagnosis and management. This article summarizes the genetic aspects of parathyroid carcinoma, reviews its clinical manifestations, and outlines the principles of surgical therapy, the indications for adjuvant therapy, and the use of bisphosphonate and calcimimetic agents for management of hypercalcemia.

Topics: Carcinoma; Cyclin D1; Genes, Retinoblastoma; Genes, Tumor Suppressor; Germ-Line Mutation; Humans; Hypercalcemia; Hyperparathyroidism; Parathyroid Hormone; Parathyroid Neoplasms; Proteins; Proto-Oncogene Proteins; Tumor Suppressor Proteins

Topics: Aminopyridines; Animals; Benzimidazoles; Carcinoma, Small Cell; Cell Line, Tumor; Cell Survival; Chromatin Immunoprecipitation; Cyclin D1; DNA Helicases; Female; Humans; Hypercalcemia; Mice; Mice, SCID; Nuclear Proteins; Ovarian Neoplasms; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; RNA, Small Interfering; Transcription Factors

Primary hyperparathyroidism (PHPT) occurs sporadically, but occasionally it may be a feature of a familial condition, such as multiple endocrine neoplasia type 1 (MEN1), MEN2A, or the HPT-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia/neonatal severe hyperparathyroidism (FHH/NSHPT). PHPT may also occur as familial isolated hyperparathyroidism (FIHP), and has been observed as a consequence of mutations in the CDKN1B gene (MEN4). Tumorigenesis in these conditions may be the result of protooncogene activation (e.g. RET in MEN2) or two-hit losses of a tumor suppressor (e.g. MEN1, HPT-JT). In patients with MEN1, HPT-JT or FHH/NSHPT, the hyperparathyroidism manifests at a younger age and affects both sexes equally. In MEN1, mutations of the MEN1 gene also cause enteropancreatic and anterior pituitary tumors. In MEN2, activating mutations in the RET protooncogene also cause medullary thyroid carcinoma and pheochromocytoma. In HPT-JT, mutations of CDC73/HRPT2 are associated with parathyroid carcinoma, but tumors of the kidneys and uterus are additional features. In some FIHP families, a CASR mutation may be identified. In parathyroid carcinoma, even if sporadic, molecular diagnostics for CDC73/HRPT2 should be considered, as it should be for younger patients. Further exploration of these hereditary syndromes may shed light on the molecular mechanisms giving rise to nonhereditary PHPT.

Topics: Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Female; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Infant, Newborn; Infant, Newborn, Diseases; Jaw Neoplasms; Loss of Heterozygosity; Male; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2a; Parathyroid Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Receptors, Calcium-Sensing; Tumor Suppressor Proteins