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Published on: March 14, 2017
Loss of parafibromin expression in a subset of parathyroid adenomas
C Juhlin1, C Larsson, T Yakoleva
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, CMM L8: 01, SE-171 76 Stockholm, Sweden.
Abstract:
Inactivation of the hyperparathyroidism-jaw tumour syndrome (HPT- JT) gene, HRPT2, was recently established as a genetic mechanism in the development of parathyroid tumours. Its encoded protein parafibromin has tumour-suppressor properties that play an important role in tumour development in the parathyroids, jaws and kidneys. Inactivating HRPT2 mutations are common in HPT- JT and parathyroid carcinomas, and have been described in a few cases of parathyroid adenomas with cystic features. In this study, 46 cases of cystic parathyroid adenomas previously investigated for HRPT2 mutations were characterized with regard to MEN1 gene mutations, cyclin D1 expression and parafibromin expression. In normal tissues and cell lines, parafibromin was ubiquitously expressed. Furthermore, parafibromin was detected as a dominating nuclear and a weaker cytoplasmic signal in transfected cell lines. In the three parathyroid tumours with inactivating HRPT2 mutations parafibromin expression was not detectable, and in one of two cases with aberrantly sized parafibromin the protein was delocalized. Both high and low cyclin D1 levels were found among HRPT2-mutated and -unmutated tumours, suggesting that these events are not mutually exclusive in parathyroid tumour development. The presented data suggest that in the majority of benign parathyroid tumours the expression of parafibromin remains unaltered, while the loss of parafibromin expression is strongly indicative of gene inactivation through mutation of the HRPT2 gene.
Insights
Loss of parafibromin expression in parathyroid tumors indicates HRPT2 gene inactivation. This finding is crucial for understanding parathyroid tumor development and the role of the hyperparathyroidism-jaw tumor syndrome gene.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- The hyperparathyroidism-jaw tumour syndrome (HPT-JT) gene, HRPT2, and its protein parafibromin are implicated in parathyroid tumor development.
- HRPT2 mutations are associated with HPT-JT, parathyroid carcinomas, and some cystic parathyroid adenomas.
- Parafibromin functions as a tumor suppressor in parathyroid, jaw, and kidney tissues.
Purpose of the Study:
- To investigate HRPT2 mutations, MEN1 gene mutations, cyclin D1 expression, and parafibromin expression in 46 cases of cystic parathyroid adenomas.
- To determine the correlation between HRPT2 mutations and parafibromin expression in parathyroid tumors.
- To explore the role of parafibromin in the pathogenesis of benign and malignant parathyroid neoplasms.
Main Methods:
- Analysis of 46 cystic parathyroid adenomas for HRPT2 and MEN1 gene mutations.
- Assessment of cyclin D1 and parafibromin protein expression using immunohistochemistry.
- Evaluation of parafibromin localization (nuclear vs. cytoplasmic) in normal tissues, cell lines, and tumor samples.
Main Results:
- Parafibromin exhibited ubiquitous expression in normal tissues and a predominantly nuclear localization in transfected cells.
- Loss of parafibromin expression was observed in parathyroid tumors with inactivating HRPT2 mutations.
- Aberrant parafibromin size and delocalization were noted in some HRPT2-mutated tumors.
- Cyclin D1 levels varied independently of HRPT2 mutation status, suggesting distinct roles in tumorigenesis.
Conclusions:
- Loss of parafibromin expression is a strong indicator of HRPT2 gene inactivation in parathyroid tumors.
- In the majority of benign parathyroid tumors, parafibromin expression remains unaltered.
- The findings reinforce the tumor-suppressor role of parafibromin and its significance in parathyroid tumorigenesis.
