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Hypermethylation of Adenosine Triphosphate-Binding Cassette Transporter Genes in Primary Hyperparathyroidism and Its Effect on Sestamibi Imaging

Department of Molecular Oncology (H.T., D.S.B.H., N.U.) and the Breast and Endocrine Program (N.C.G., N.M.H., A.E.G., F.R.S.), John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California 90404

Address all correspondence and requests for reprints to: Frederick Singer, M.D., John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, California 90404. E-mail: singerf{at}jwci.org.

Context: Retention of technetium-^99m-sestamibi (^99mTc-sestamibi) by parathyroid adenomas appears to be due to the loss of at least one membrane transporter, multidrug resistance 1 (MDR1), and possibly another, multidrug resistance-associated protein 1 (MRP1).

Objective: The objective was to determine whether hypermethylation of either gene plays a role in their expression and ^99mTc-sestamibi retention.

Design: This was a retrospective study on a convenience sample of paraffin-embedded parathyroid glands.

Setting: The study was performed at the John Wayne Cancer Institute at Saint John’s Health Center (Santa Monica, CA).

Patients: Forty-eight patients with primary hyperparathyroidism and five patients without parathyroid disease undergoing thyroid surgery provided 27 adenomatous, 10 hyperplastic, and 16 normal parathyroid glands.

Intervention: We performed immunohistochemistry, real-time quantitative RT-PCR, and methylation-specific PCR for MDR1 and MRP1 on archival parathyroid tissue and correlated these results with the patient’s ^99mTc-sestamibi scan.

Main Outcome Measure: The main outcome measure was to determine whether hypermethylation of the genes for either transporter is associated with loss of their expression and with a positive ^99mTc-sestamibi scan.

Results: The MDR1 gene was methylated in none of 12 normal glands, 19 of 27 adenomas, and three of 10 hyperplastic glands. Methylation of the MRP1 gene was uncommon (five of 48 tested glands). Methylation of the gene affected the transcript level only for MDR1. Among all glands, hypermethylation for MDR1 was more likely in ^99mTc-sestamibi-positive scans (P < 0.001).

Conclusion: In parathyroid tissue, hypermethylation of the MDR1 gene decreases its expression and is associated with increased detection of parathyroid adenomas by ^99mTc-sestamibi parathyroid scans.