Title

Genomic screening for parathyroid tumor suppressor gene and candidate gene analysis

Date of Completion

January 2006

Keywords

Biology, Molecular|Biology, Genetics|Health Sciences, Oncology

Degree

Ph.D.

Abstract

The molecular pathogenesis of parathyroid adenomas has yet to be fully elucidated with only two genes, cyclin D1 and MENI , established as direct contributors to the pathogenesis of sporadic parathyroid adenomas. Parathyroid adenomas are often solitary benign neoplasms that commonly cause primary hyperparathyroidism. Studies of adenomas, including data from our lab, have demonstrated recurrent genetic losses on chromosomes 1p, 6q, 9p, 11q, 12q, 13q, and 15q, implying that novel tumor suppressor genes are localized on these chromosomes and potentially contribute to the tumorigenesis of parathyroid glands. ^ Previous studies, using CGH analysis demonstrated LOH of chromosome 12, near the VDR gene. Dinucleotide microsatellite and DNA sequencing analysis demonstrated neither evidences for loss of heterozygosity nor evidence of intragenic, somatic mutations within the VDR gene. These results suggest that loss of function mutations within the VDR gene may not act commonly, if at all, as a primary driver of clonal parathyroid growth in the development of typical parathyroid adenomas. ^ Affymetrix® SNP Chips were utilized for a high-resolution, genome-wide analysis of sporadic parathyroid adenomas and constitutional DNA from the same individuals. Regions of LOH on chromosome 15 tended to be complex, with 9 distinct regions of LOH demarcated among 10 genetically informative sample pairs. Significantly, 1 region of LOH was localized to 15g26.1, a region of loss previously identified by CGH analysis. This region of loss harbored a novel gene UNQ9370. DNA sequencing analysis demonstrated no evidence of intragenic mutations within the gene; therefore, it is concluded that UNQ9370 is unlikely to act as a classic tumor suppressor gene in sporadic parathyroid adenomas.^