Mutational Analysis of the Vitamin D Receptor Does Not Support Its Candidacy as a Tumor Suppressor Gene in Parathyroid Adenomas

Context: The vitamin D receptor gene (VDR) is a compelling candidate tumor suppressor gene for parathyroid adenomas based on existing evidence of the vitamin D system’s antiproliferative actions in parathyroid and other tissues, its reported inhibition of PTH gene transcription, and the decreased expression of VDR mRNA and VDR protein observed in parathyroid adenomas. Objective: Because demonstration of intragenic mutations is required to establish the authenticity and primary role in pathogenesis for any candidate tumor suppressor gene, we examined the VDR gene in parathyroid adenomas for the presence of such mutations and other loss-of-function abnormalities. Methods and Results: Genomic DNA samples from 37 sporadic parathyroid adenomas and matched normal control DNA from the same individuals were subjected to direct sequencing of the entire VDR coding region and all intron-exon boundaries. No VDR coding region or junctional mutations were identified. The tumors were also analyzed for loss of heterozygosity, a frequent mechanism of tumor suppressor gene inactivation, by molecular allelotyping at three microsatellite markers located near the VDR gene, D12S85, D12S96, and D12S368, and a polymorphism within VDR itself. In all 37 cases, at least one marker was informative and no tumor-specific loss of heterozygosity was observed. Conclusion: We found no evidence of allelic loss within or near the VDR locus and no mutations within the splice junctions and coding regions of the VDR gene in 37 typical sporadic parathyroid adenomas. Thus, VDR is most unlikely to commonly serve as a classical tumor suppressor gene in sporadic parathyroid adenomas.