Aberrant Methylation of the HRPT2 Gene in Parathyroid Carcinoma

Objectives: The incidence of parathyroid carcinoma in hyperparathyroidism-jaw tumor syndrome (HPT-JT) is reported to be as high as 15%. We used a methylation-specific polymerase chain reaction (MS-PCR) technique to investigate whether hypermethylation is one mechanism of HRPT2 gene inactivation in parathyroid tumors.

Methods: DNA was extracted from samples of parathyroid tumors embedded in paraffin. MS-PCR was performed on 11 parathyroid carcinomas, 37 sporadic parathyroid adenomas from control subjects, and 6 parathyroid adenomas from 3 patients with HPT-JT. Methylated and unmethylated PCR products from 2 tumors (Nos. 2 and 6) were cloned. Clones containing inserts were sequenced.

Results: Two of 11 (18%) parathyroid carcinomas showed amplification patterns consistent with methylation, compared to 0 of 37 sporadic parathyroid adenomas, and 1 of 6 (17%) parathyroid tumor samples from 3 HPT-JT patients. These results were confirmed by sequencing multiple clones from each of these samples.

Conclusions: There is increasing evidence that loss of HRPT2 gene expression is strongly associated with parathyroid carcinomas. Our data indicate that methylation of the HRPT2 promoter may be another mechanism by which HRPT2 gene inactivation gives rise to parathyroid carcinomas.