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.