Secondary or tertiary hyperparathyroidism is a major medical concern, causing increased morbidity and mortality for patients with chronic kidney disease (CKD). The goal of this project is to localize and potentially identify the genetic changes which cause benign hyperplastic growth of the parathyroids in patients with severe secondary/tertiary hyperparathyroidism. The hypothesis that parathyroid outgrowths in secondary/tertiary hyperparathyroidism are caused by genetic changes resulting in a selective growth advantage is supported by previous work which has shown that most patients harbor at least one monoclonal parathyroid growth. Such clonal expansions develop from a single cell which acquired a selective growth advantage and the gene(s) responsible for this uncontrolled growth can be localized and potentially identified through determining chromosomal copy number changes and gene expression changes. Preliminary studies have illustrated large regions of acquired chromosomal gains and losses in hypercellular glands from patients with secondary/tertiary hyperparathyroidism but the specific contributing genes remain unknown. Through higher resolution techniques such as the Affymetrix 500K SNP Microarray, and whole genome expression analysis, we aim: 1) To uncover the molecular changes which may be responsible for secondary/tertiary parathyroid outgrowths by examining chromosomal copy number;and 2) To further the identification of potential growth inhibitory or activation genes by expression analysis, a) investigating genes with decreased expression through alignment of expression data with our regions of DMA loss;b) pursuing the presence of oncogenes through alignment of our expression data with our results of copy number gain;and c) searching for genes involved in chromosomal translocation that would not be uncovered in copy number analysis. Ultimately, knowledge of the molecular basis of severe secondary/tertiary hyperparathyroidism may lead to new diagnostic, prognostic, and treatment strategies for the numerous patients with CKD who suffer from secondary/tertiary hyperparathyroidism. Public Health Significance: Many patients with renal disease develop severe secondary or tertiary hyperparathyroidism. Through studying their pathologic parathyroid glands, we will aim to uncover mechanisms of this benign aberrant cell growth. Ultimately, identification of the gene(s) contributing to this disease will provide us with new diagnostic and treatment strategies.
|Lauter, Kelly; Arnold, Andrew (2009) Analysis of CYP27B1, encoding 25-hydroxyvitamin D-1alpha-hydroxylase, as a candidate tumor suppressor gene in primary and severe secondary/tertiary hyperparathyroidism. J Bone Miner Res 24:102-4|