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RET is expressed but not mutated in extra-adrenal paragangliomas
R R de Krijger1, E van der Harst, S Muletta-Feurer
1Department of Pathology, Erasmus University and University Hospital, Rotterdam, The Netherlands. dekrijger@path.fgg.eur.nl
Abstract:
This study has investigated the role of the RET proto-oncogene, which has been identified as the susceptibility gene for multiple endocrine neoplasia (MEN) type 2, in the development of sporadic and familial extra-adrenal paragangliomas. RET protein expression was analysed by immunohistochemistry. Subsequently, DNA extracted from 52 tumours of 44 patients was screened for somatic RET point mutations in exons 10, 11, and 13-16, where oncogenic mutations have recently been described in a subset of sporadic medullary thyroid carcinomas and phaeochromocytomas. The methods employed included non-isotopic polymerase chain reaction-based single strand conformation polymorphism (PCR-SSCP) analysis and heteroduplex gel electrophoresis, followed by direct sequencing of PCR products. RET protein expression was demonstrated in all ten paragangliomas tested. However, none of the familial or sporadic extra-adrenal paragangliomas contained somatic mutations in exons 10, 11, or 13-16 of the RET proto-oncogene, whereas control samples with known mutations in these exons exhibited the expected band shift, or yielded an additional band with retarded migration. Although paragangliomas exhibit RET protein expression, these data indicate that oncogenic RET proto-oncogene mutations do not appear to be generally important in the formation of sporadic paragangliomas.
Insights
This study examined the RET proto-oncogene in paragangliomas. Oncogenic RET mutations were not found to be a significant factor in the development of these tumors, despite RET protein expression.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- The RET proto-oncogene is linked to Multiple Endocrine Neoplasia type 2.
- Its role in sporadic and familial extra-adrenal paragangliomas is not fully understood.
Purpose of the Study:
- To investigate the involvement of the RET proto-oncogene in the development of sporadic and familial extra-adrenal paragangliomas.
- To screen for somatic RET point mutations in specific exons known to harbor oncogenic mutations.
Main Methods:
- Immunohistochemistry was used to analyze RET protein expression.
- DNA from 52 tumors was screened for RET mutations using PCR-SSCP and heteroduplex gel electrophoresis, followed by sequencing.
- Control samples with known mutations were used for validation.
Main Results:
- RET protein expression was detected in all tested paragangliomas.
- No somatic RET mutations were identified in exons 10, 11, or 13-16 of familial or sporadic paragangliomas.
- Control samples confirmed the mutation detection methodology.
Conclusions:
- While paragangliomas express RET protein, oncogenic RET proto-oncogene mutations are not a general cause of sporadic paraganglioma formation.
- Further research may be needed to explore other genetic factors involved in paraganglioma development.