Hypermethylation of adenosine triphosphate-binding cassette transporter genes in primary hyperparathyroidism and its effect on sestamibi imaging.
BACKGROUND
Retention of technetium-(99m)-sestamibi ((99m)Tc-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 (99m)Tc-sestamibi retention.


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


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


METHODS
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.


METHODS
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 (99m)Tc-sestamibi scan.


METHODS
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 (99m)Tc-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 (99m)Tc-sestamibi-positive scans (P < 0.001).


CONCLUSIONS
In parathyroid tissue, hypermethylation of the MDR1 gene decreases its expression and is associated with increased detection of parathyroid adenomas by (99m)Tc-sestamibi parathyroid scans.
Takeuchi
Hiroya
H
Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA.
Greep
Nancy C
NC
Hoon
Dave S B
DS
Giuliano
Armando E
AE
Hansen
Nora M
NM
Umetani
Naoyuki
N
Singer
Frederick R
FR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000236:Adenoma / Q000000981:diagnostic imaging / Q000473:pathology; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000000981:diagnostic imaging* / Q000235:genetics*; D007150:Immunohistochemistry; D008745:Methylation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010280:Parathyroid Glands / Q000000981:diagnostic imaging / Q000473:pathology; D010282:Parathyroid Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017256:Technetium Tc 99m Sestamibi
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012313:RNA; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; C421109:multidrug resistance-associated protein 1