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Vitamin D Receptor as a Candidate Tumor-Suppressor Gene in Severe Hyperparathyroidism of Uremia¹

Center for Molecular Medicine and Division of Endocrinology and Metabolism, University of Connecticut School of Medicine (S.B.B., T.T.B., A.A.), Farmington, Connecticut 06030-3101; Memorial Sloan-Kettering Cancer Center (N.P., R.S.K.C.), New York, New York 10021; University of California Medical Center (I.S., W.G.), Los Angeles, California 90095; University of Florence (M.L.B.), 50139 Florence, Italy; Hôpital Necker (T.B.D., P.U.), 75743 Paris, France; Hôpital St. Louis (E.S.), 75475 Paris, France; and University of Cincinnati (J.W.P), Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Dr. Andrew Arnold, Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-3101.

Most chronic renal failure patients with severe refractory hyperparathyroidism harbor at least one monoclonal parathyroid tumor, but the specific acquired genetic defects that confer this clonal selective advantage remain poorly understood. Somatic inactivation of the vitamin D receptor (VDR) gene could contribute to clonal outgrowth, because a parathyroid cell containing this lesion would have an impaired response to the antiproliferative influence of 1,25-dihydroxyvitamin D₃. Furthermore, diminished expression of VDR protein has been described in uremia-associated parathyroid tumors. Therefore, to assess VDR gene inactivation’s potential pathogenetic role in this disease, we rigorously analyzed the VDR gene in 59 parathyroid tumors surgically resected from uremic patients.

First, Southern blotting and/or PCR analyses of 29 tumor samples from 14 genetically informative patients revealed no allelic losses at the VDR locus. Next, direct DNA sequencing of all VDR splice junctions, associated intronic sequences, and virtually the entire VDR-coding region for all 59 tumors revealed no acquired mutations. Last, 37 tumor DNA samples were subjected to comparative genomic hybridization, and no chromosomal losses in the VDR region (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 hyperparathyroidism in uremia.

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