Title

Molecular pathogenesis of parathyroid neoplasia

Date of Completion

January 2009

Keywords

Biology, Molecular

Degree

Ph.D.

Abstract

The molecular basis of both benign and malignant parathyroid neoplasia is still poorly understood. While a few genes have been identified whose alteration contributes to parathyroid tumor formation, many of the genetic and genomic contributors remain unknown. It remains controversial whether benign adenomas are actually capable of progressing to frank cancer or if parathyroid cancers arise de novo, without passing through an adenoma intermediate. ^ Through genome-wide copy number and loss of heterozygosity analyses using Affymetrix GeneChip SNP mapping arrays, this study identified regions of likely genetic importance to the pathogenesis of parathyroid tumors. Tumor suppressor genes contributing to benign parathyroid tumorigenesis are likely located on chromosomes 1, 6q, 9, 11, 13q, 15q, 18q and 22q. Chromosomes 1p, 3, 13q and 14q likely contain tumor suppressor genes important to malignant parathyroid tumorigenesis. Chromosomes 1, 11 and 13 likely contain more than one tumor suppressor gene relevant to parathyroid tumorigenesis. ^ Based on the pattern of clonal allelic alterations in parathyroid tumors, it is likely that the majority of malignant parathyroid carcinomas arise independently of, rather then as a progression from, benign parathyroid Jessica Costa-University of Connecticut, 2009 adenomas. It is unclear whether a subset of parathyroid adenomas could have malignant potential. ^ Mutational analysis of CDKN1B, encoding p27, revealed both germline and somatic mutations in seemingly sporadic parathyroid adenomas, highlighting its role as an important contributor to benign parathyroid tumorigenesis. Sequence analyses have also excluded the involvement of several important candidate genes in parathyroid tumorigenesis. No mutations of CTNNB1 exon 3 were found in 97 parathyroid adenomas and 10 parathyroid carcinomas, illustrating that involvement of β-catenin mutation in parathyroid tumorigenesis is, at best, exceedingly rare. Mutations of HRAS, KRAS NRAS, BRAF, TP53 and PTEN were not found in parathyroid carcinomas. It is likely that mutation of these genes contribute infrequently, if at all, to the molecular pathogenesis of parathyroid carcinoma. Somatic mutations miR-15a-miR-16-1 were not found in parathyroid carcinomas; a gene or genes other than miR-15a-miR-16-1 is likely the primary target of allelic loss of chromosome 13 in parathyroid cancers. ^