Genetics of Hyperparathyroidism, Including Parathyroid Cancer

Abstract

Primary hyperparathyroidism (HPT) is a metabolic disease caused by the excessive secretion of parathyroid hormone from 1 or more neoplastic parathyroid glands. HPT is largely sporadic, but it can be associated with a familial syndrome. The study of such families led to the discovery of tumor suppressor genes whose loss of function is now recognized to underlie the development of many sporadic parathyroid tumors. Heritable and acquired oncogenes causing parathyroid neoplasia are also known. Studies of somatic changes in parathyroid tumor DNA and investigation of kindreds with unexplained familial HPT promise to unmask more genes relevant to parathyroid neoplasia.

Keywords: CCND1; CDC73; MEN1; MEN2A; Multiple endocrine neoplasia; Oncogene; RET; Tumor suppressor.

Figure 1. Two-hit loss of function mutation of the CDC73/HRPT2 tumor suppressor in parathyroid neoplasia

Benign or malignant parathyroid tumors causing hyperparathyroidism (HPT) can result from two-hit loss of function of the CDC73/HRPT2 tumor suppressor gene according to the Knudson hypothesis (see text). The human CDC73/HRPT2 gene is on chromosome 1 at location 1q25. Upper: In a patient without germline CDC73/HRPT2 mutation, both alleles of CDC73/HRPT2 are initially normal in all parathyroid cells. Subsequent step-wise acquired or somatic inactivation of both alleles in the same parathyroid cell results in clonal expansion that may lead to a sporadic parathyroid tumor. Lower: In a patient with germline CDC73/HRPT2 mutation in one allele, an acquired or somatic DNA mutation at the CDC73/HRPT2 locus of the remaining allele in a parathyroid cell results clonal expansion of that cell that may lead to a benign or malignant parathyroid tumor. Patients with germline CDC73/HRPT2 mutation who develop parathyroid adenomas or cancer can present sporadically (if lacking or unaware of relevant family medical history), or belong to a kindred with familial isolated HPT or the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The presence of the first germline mutation at birth in all parathyroid tissue accelerates the acquisition of two hits within a single parathyroid cell and accounts for the earlier age of disease presentation typical of familial forms of HPT such as HPT-JT.