Title

Molecular pathogenesis of parathyroid neoplasia

Date of Completion

January 2006

Keywords

Biology, Genetics|Health Sciences, Medicine and Surgery

Degree

Ph.D.

Abstract

Primary hyperparathyroidism commonly results from a benign adenoma of the parathyroid gland and rarely from malignant parathyroid carcinomas, but the two neoplasms can be difficult to distinguish in patients lacking distant metastases. While several genes clearly play identified roles in the pathogenesis of parathyroid adenomas, no gene has been definitively shown to be involved in parathyroid carcinogenesis. Acquired chromosomal changes identified in parathyroid adenomas and carcinomas define areas in the genome that may house tumor suppressor genes important for the pathogenesis of parathyroid neoplasia. Discovery of genetic changes unique to adenomas or carcinomas will further the understanding of parathyroid tumorigenesis and eventually may promote the discovery of new clinical markers and treatments. ^ This research sought to better define the importance of chromosome 13 in the pathogenesis of parathyroid carcinomas and adenomas and HRPT2 in carcinomas. High resolution LOH analysis of chromosome 13 on a large set of parathyroid adenomas and carcinomas indicated that loss of chromosome 13 is a more frequent event in parathyroid carcinomas than adenomas. Regions of chromosome 13 LOH tended to be very large, but two distinct chromosome 13 parathyroid tumor suppressors may exist. In parathyroid carcinomas, an identified region of loss contained approximately 34MB of genetic information including two known tumor suppressor genes, RB and BRCA2, and several genes whose function suggests a possible role in parathyroid tumorigenesis, FKHR, TSC-22, and DRIP36. None of these genes displayed mutations that supported its role as a tumor suppressor gene. Custom microarrays of cDNAs from the chromosome 13 region identified additional interesting candidate genes and ESTs having altered expression in multiple parathyroid carcinomas with chromosome 13 loss. Expression analysis of 4,600 genes in parathyroid carcinomas with chromosome 13 loss highlighted a subset of genes that is altered in all or several of the parathyroid carcinomas, indicating possible primary or secondary players in the evolution of these tumors. Finally, the HRPT2 tumor suppressor gene was found to be frequently mutated in sporadic parathyroid carcinomas representing the identification of the first genetic contributor to the pathogenesis of parathyroid carcinoma and the most frequently mutated gene in parathyroid tumors discovered to date. ^

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