Chromosome 11 genomic changes in parathyroid adenoma and hyperplasia: Array CGH, FISH, and tissue microarrays

Abstract

We have used a combination of gene expression profiling, array comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH) and tissue microarrays (TMAs) to investigate chromosome 11 genetic changes in subsets of benign parathyroid tumors. Integration of gene expression profiling and aCGH was done using differential gene locus mapping analysis. We have identified three distinct relatively common chromosome 11 genomic changes in various subsets of parathyroid tumors. The simplest and least common of these genomic changes involves translocation of the CCND1 gene with subsequent strong CCND1 expression. This genetic change is essentially limited to parathyroid adenomas (8%), although expression of CCND1 without translocation is common in uremic hyperparathyroidism. Not surprisingly, deletion of the MEN1 locus at 11q13 or loss of a large portion or an entire chromosome 11 was a common finding. This particular genomic change appears to have a prominent effect on the overall results of gene expression profiling and was present in slightly less than one-half of adenomas. Genomic changes in primary nonfamilial hyperplasia were for the most part restricted to 11q13 deletion or loss of chromosome 11. The third genomic change we identified was 11q23 deletion. This genetic change was relatively independent of other chromosome 11 changes and present in slightly less than one-half of adenomas. 11q23 deletion along with relatively strong CCND1 expression was common in uremic hyperparathyroidism.

Tissue-specific regulatory regions of the PTH gene localized by novel chromosome 11 rearrangement breakpoints in a parathyroid adenoma

“…The present study shows that such breakpoints do indeed exist in parathyroid adenomas, and that past analyses likely underestimated the true prevalence of PTH-cyclin D1 rearrangements in parathyroid adenomas. Indeed, using interphase FISH which can detect breakpoints over a large chromosome segment, cyclin D1 rearrangements can be detected in as many as 8% of parathyroid adenomas (40). Such rearrangements are associated with increased cyclin D1 expression, further emphasizing cyclin D1’s role as the target oncogene in this region.…”

Clinical and molecular genetics of parathyroid neoplasms

“…In studies that looked at loss of heterozygosity at 11q13 in sporadic adenomas, the frequency ranged from 26-37%. A small percentage of patients with apparently sporadic parathyroid adenomas are demonstrated to harbor a germline mutation of MEN1 [26-32]. Since HPT is usually the earliest and most penetrant feature of MEN1, kindreds may rarely be assigned a provisional diagnosis of familial isolated primary hyperparathyroidism if only younger MEN1 mutation carriers are considered at the time of family ascertainment (see below).…”

Germline and Somatic Mutations in Cyclin-Dependent Kinase Inhibitor Genes CDKN1A, CDKN2B, and CDKN2C in Sporadic Parathyroid Adenomas

“…Peri-centromeric rearrangement of chromosome 11, which places the cyclin D1 coding exons under direct regulation of the parathyroid hormone ( PTH ) gene regulatory region, occurs in ~8 % of parathyroid adenomas [4, 5], and cyclin D1 activation by this and other mechanisms has been observed in 20–40 % of adenomas. Cyclin D1, together with partner cyclin-dependent kinases (CDKs), regulates the G1 to S phase transition of the cell cycle, which raised the candidacy of CDK inhibitors (CDKIs) as potential parathyroid tumor genes.…”