Vitamin D receptor as a candidate tumor-suppressor gene in severe hyperparathyroidism of uremia

Most chronic renal failure patients with severe refractory hyperparathyroid ism harbor at least one monoclonal parathyroid tumor, but the specific acqu ired genetic defects that confer this clonal selective advantage remain poo rly understood. Somatic inactivation of the vitamin D receptor (VDR) gene c ould contribute to clonal outgrowth, because a parathyroid cell containing this lesion would have an impaired response to the antiproliferative influe nce of 1,25-dihydroxyvitamin D-3. Furthermore, diminished expression of VDR protein has been described in uremia-associated parathyroid tumors. Theref ore, to assess VDR gene inactivation's potential pathogenetic role in this disease, we rigorously analyzed the VDR gene in 59 parathyroid tumors surgi cally resected from uremic patients. First, Southern blotting and/or PCR analyses of 29 tumor samples from 14 ge netically informative patients revealed no allelic losses at the VDR locus. Next, direct DNA sequencing of all VDR splice junctions, associated intron ic sequences, and virtually the entire VDR-coding region for all 59 tumors revealed no acquired mutations. Last, 37 tumor DNA samples were subjected t o comparative genomic hybridization, and no chromosomal losses in the VDR r egion (12cen-q12) were observed. These observations suggest that inactivating defects within the VDR gene do not commonly contribute to the primary pathogenesis of severe refractory h yperparathyroidism in uremia.