Molecular Genetic Abnormalities in Sporadic Hyperparathyroidism

Abstract

The biochemical state of primary hyperparathyroidism is generally caused by hypercellular parathyroid glands categorized as multigland hyperplasia, benign adenoma or malignant carcinoma. Most, and probably all, adenomas and carcinomas are monoclonal in origin, and specific clonal genetic lesions have been identified in most of these tumors. Only two genes have been definitively proven to be important players in the pathogenesis of typical sporadic parathyroid tumors, an oncogene, cydin D1 and a tumor suppressor gene, MEN1. The cyclin D1 oncoprotein is overexpressed in 20–40% of parathyroid adenomas and the identification of clonal rearrangements which activate the cyclin D1 gene in a subset of tumors indicates that such activation is a primary genetic driver of parathyroid neoplasia. Cyclin D1 plays an important role in regulation of the cell cycle and may have non-cell cycle effects which contribute to tumorigenesis as well. The central role that cyclin D1 plays in parathyroid tumorigenesis has been confirmed in a mouse model where cyclin D1 is overexpressed specifically in the parathyroids and in which many features of human hyperparathyroidism are reproduced. Germline mutations of MEN1 cause multiple endocrine neoplasia type 1, a genetic syndrome in which patients develop tumors of multiple endocrine (and some nonendocrine) tissues including the parathyroid glands. Acquired (somatic) mutations in MEN1 have also been identified in 12–17% of sporadic parathyroid adenomas. The function of MEN1 remains elusive, but the discovery of proteins that interact with the MEN1 protein product, menin, and the development of a mouse model of MEN1 syndrome may help to shed light on menin’s function. The HRPT2 gene has recently been identified as a major contributor to the development of sporadic parathyroid carcinoma. Identification of acquired chromosomal aberrations in parathyroid adenomas and carcinomas using techniques such as molecular allelotyping and comparative genomic hybridization has highlighted several areas of the genome that may harbor other important parathyroid tumor suppressor genes and oncogenes. The eventual identification of the full spectrum of genes involved in parathyroid tumorigenesis will be important for developing a complete understanding of the molecular basis of primary hyperparathyroidism.