Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid hyperplasia caused by chronic renal failure versus primary adenoma.
BACKGROUND
In primary hyperparathyroidism, certain genetic abnormalities responsible for parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary parathyroid adenomas. However, in secondary hyperparathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia.


METHODS
In adenomas (N = 15) and associated glands (N = 7) with normal histology obtained from patients with primary hyperparathyroidism and in diffuse (N = 14), multinodular (N = 58), and single nodular (N = 28) glands from patients who underwent parathyroidectomy for renal hyperparathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody.


RESULTS
In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 (P < 0.05), retinoblastoma gene products (P < 0.05), and Ki67 (P < 0.05). However, no statistically significant correlation between the expression of PRAD1/cyclin D1 and that of Ki67 was observed in both primary adenoma and secondary hyperplasia.


CONCLUSIONS
These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene.
Tominaga
Y
Y
Department of Transplant Surgery and Pathology, Nagoya Second Red Cross Hospital, Japan.
Tsuzuki
T
T
Uchida
K
K
Haba
T
T
Otsuka
S
S
Ichimori
T
T
Yamada
K
K
Numano
M
M
Tanaka
Y
Y
Takagi
H
H
D000236:Adenoma / Q000150:complications* / Q000378:metabolism / Q000648:ultrastructure; D014408:Biomarkers, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000096:biosynthesis*; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D007676:Kidney Failure, Chronic / Q000150:complications*; D008875:Middle Aged; D010280:Parathyroid Glands / Q000378:metabolism* / Q000473:pathology; D010282:Parathyroid Neoplasms / Q000150:complications* / Q000378:metabolism / Q000648:ultrastructure; D000090063:Proto-Oncogene Mas; D016160:Retinoblastoma Protein / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016160:Retinoblastoma Protein; D019938:Cyclin D1