Parathyroid disease and tumor formation can occur both as a primary process and as a complication of chronic renal failure. Monoclonality has been demonstrated in not only primary parathyroid tumors, but also in a portion of secondary/tertiary tumors. Although multiple genes have been implicated in parathyroid disease, the genetic basis of a large portion of tumors remains unknown. In this dissertation, we investigated the genetic basis of primary and secondary/tertiary parathyroid disease.

We investigated severe secondary/tertiary parathyroid disease through whole-genome microarray analysis of chromosomal change in 48 tumors and uncovered large regions of chromosomal amplification and deletion. Additionally, we sequenced the putative tumor suppressor genes CDKN1B, CYP27B1, and the PTH 3'UTR and demonstrated an absence of mutations in each.

We also surveyed the genetic changes in sporadic atypical parathyroid adenomas, which possess similarities to parathyroid carcinoma. Since the HRPT2 gene is responsible for tumorigenesis in the vast majority of sporadic parathyroid carcinomas, we asked whether atypical adenomas would harbor the same mutation. We sequenced the HRPT2 gene in 10 atypical adenomas and used immunohistochemistry to investigate its protein product, parafibromin, in 12 tumors. We found no alterations in the genetic sequence and no differences in parafibromin staining. We also analyzed 5 atypical adenomas with microarray technology, finding only large regions of genomic change. We therefore concluded that atypical adenoma is indeed a distinct entity, differing genetically from carcinoma.

Similarly, we studied parathyromatosis in an effort to uncover the genetic basis of the disease and determine if it is a precursor lesion for carcinoma. We sequenced HRPT2 in 9 cases of parathyromatosis and investigated parafibromin staining, finding no sequence or staining alterations. Thus, though it has the ability to seed and recur, parathyromatosis is a distinct disease, which differs genetically from parathyroid carcinoma.

Additionally, we investigated the 1 lql3 region containing the MEN1 tumor suppressor gene and the Cyclin D1 oncogene. Through FISH and LOH analysis, we were able to identify a tendency for chromosomal breakage in 1/6 of tumors. In two of the tumors, we have been able to isolate the breakpoints to 9.8 kb and 94 kb regions.