MOLECULAR BIOLOGIC STUDIES ON THE CAUSE OF PARATHYROID NEOPLASIA

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Primary hyperparathyroidism (HPT), a common endocrine disorder that can cause significant morbidity, may be due to benign neoplasia of a single parathyroid gland (adenoma) or multiple parathyroid glands (hyperplasia), and rarely, to malignant neoplasia of a parathyroid gland (carcinoma). The etiology of parathyroid neoplasia has not been defined. As with other forms of neoplasia, parathyroid tumors are presumably due to inherited (germ-line mutation) and/or acquired (somatic mutation) defects in specific genes. Etiologic genetic defects could include inappropriate expression of transforming "oncogenes" and/or loss of expression of tumor "suppressor" genes. The availability of surgically resected parathyroid tumors from patients with sporadic and hereditary forms of disease allows us to search for tumor-specific genetic abnormalities that may be involved in develop- ment of parathyroid neoplasia. We have found rearrangement of the parathyroid hormone gene in only 1 of 43 parathyroid adenomas, but this gene abnormality may be pathogenetically relevant. In contrast, point mutations in ras oncogenes were not found in any parathyroid tumors. In both "hyperplastic" glands from subjects with inherited multiple endocrine neoplasia type I (MEN I) and in sporadic adenomas, loss of heterozygosity for loci on chromosome llql3 was found. The data show that tumors in MEN I are monoclonal, and that a locus in llql3 may encode a tumor "suppressor" gene. we are attempting to identify the MEN I gene among other methods by mapping deletions at llql3 in parathyroid tumors.