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Glucocorticoid receptor gene polymorphisms in ACTH-secreting pituitary tumours
S R R Antonini1, A C Latronico, L L K Elias
1Department of Paediatrics, School of Medicine of Ribeirao Preto-USP, Ribeirao Preto, Brazil.
Objective:
The inhibitory action of glucocorticoids on the hypothalamic-pituitary axis is disrupted in ACTH-secreting pituitary tumours. The molecular events leading to the development of these tumours and their relative resistance to glucocorticoids are unknown. We investigated the presence of mutations and polymorphisms of the glucocorticoid receptor (GR) gene in corticotropinoma and their possible relationship with the tissue-specific resistance to glucocorticoids.
Design And Methods:
DNA or RNA was extracted from 18 corticotropinomas and the GR gene was amplified by the polymerase chain reaction (PCR) or reverse transcriptase-PCR followed by automated direct sequencing.
Results:
We did not identify any mutation in the coding region and the exon-intron boundary regions of the GR gene. The polymorphism AAT > AGT at codon 363 (N363S) was found in 17% and the polymorphism AAT > AAC at codon 766 (N766N) in 11% of tumours, both in heterozygous state. The polymorphisms at codons 22 and 23, at introns 3 and 4, and at codon 618, previously described in normal population, were not observed.
Conclusions:
Our results show that GR gene mutations are rare and unlikely to contribute to the glucocorticoid resistance observed in corticotropinomas. Polymorphisms in the GR gene might confer a selective advantage to tumorigenesis in corticotropinoma. However, there was no relationship between GR gene polymorphism and clinical presentation, tumour size or surgery outcome, suggesting that tumour growth may not be directly related to alterations of the GR gene structure.
Insights
Glucocorticoid receptor (GR) gene mutations are rare in ACTH-secreting pituitary tumors. While polymorphisms may play a role in tumor development, they do not appear to influence clinical presentation or outcomes.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- ACTH-secreting pituitary tumors disrupt the hypothalamic-pituitary axis's response to glucocorticoids.
- The molecular basis for corticotropinoma development and glucocorticoid resistance remains unclear.
Purpose of the Study:
- To investigate glucocorticoid receptor (GR) gene mutations and polymorphisms in corticotropinomas.
- To explore the potential link between GR gene alterations and tissue-specific glucocorticoid resistance.
Main Methods:
- DNA and RNA were extracted from 18 corticotropinomas.
- The GR gene was amplified using PCR and reverse transcriptase-PCR.
- Automated direct sequencing was employed to analyze the GR gene.
Main Results:
- No mutations were found in the coding or exon-intron boundary regions of the GR gene.
- Polymorphisms N363S (17%) and N766N (11%) were identified in heterozygous states.
- Previously described polymorphisms at other sites were not observed in the tumors.
Conclusions:
- GR gene mutations are uncommon and unlikely to cause glucocorticoid resistance in corticotropinomas.
- GR gene polymorphisms may contribute to corticotropinoma tumorigenesis.
- No correlation was found between GR gene polymorphisms and clinical features or surgical outcomes.