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Increased menin expression in sporadic pituitary adenomas
Christian Wrocklage1, Heidrun Gold, Wolfgang Hackl
1Institute of Neuropathology, University Hospital, Domagkstrasse 19, D-48129 Münster, Germany.
Background:
Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour-suppressor gene are responsible for multiple endocrine neoplasia type 1, and menin, the MEN1 gene product, is usually downregulated or truncated in MEN1-associated adenomas. In contrast, exonic MEN1 mutations seem to be very rare in sporadic (MEN1-unrelated) pituitary adenomas, and it has been suggested that menin does not play a major role in these tumours. However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms.
Patients And Measurements:
We screened MEN1 coding regions and flanking intronic sequences of 136 sporadic pituitary adenomas by temporal temperature gradient gel electrophoresis (TTGE) and studied menin expression by immunoblotting in 11 of these tumours.
Results:
Sequencing of DNAs showing aberrant migration on TTGE revealed five somatic MEN1 mutations, including two missense mutations (F134L, E530K), a 2-bp deletion in exon 10 (c.1567-1568del) leading to a premature stop codon, and two 3-bp deletions in intron 5 (g.5236-5238del, g.5237-5239del). These mutations have not been reported previously in studies analysing the MEN1 gene. Immunoblotting showed menin upregulation in all adenomas examined (including one case with a missense mutation) from 1.7-fold to 10.4-fold (mean, 4.2-fold) compared to non-neoplastic adenohypophysis.
Conclusions:
Our data suggest that neither MEN1 mutations nor menin downregulation play a significant role in the development of sporadic pituitary adenomas.
Insights
Neither multiple endocrine neoplasia type 1 (MEN1) gene mutations nor menin protein downregulation appear to significantly contribute to sporadic pituitary adenoma development. Further research is needed to understand the underlying mechanisms of these tumors.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Germline mutations in the multiple endocrine neoplasia type 1 (MEN1) gene cause MEN1 syndrome, with menin (the gene product) often downregulated or truncated in associated tumors.
- Exonic MEN1 mutations are rare in sporadic pituitary adenomas, suggesting menin may not be a primary driver in these tumors.
- Alternative mechanisms like intronic mutations or epigenetic changes could potentially downregulate menin in sporadic pituitary adenomas.
Purpose of the Study:
- To investigate the role of MEN1 gene mutations and menin protein expression in the development of sporadic pituitary adenomas.
- To screen for novel MEN1 mutations in sporadic pituitary tumors.
- To assess menin protein levels in these adenomas.
Main Methods:
- Screening of MEN1 coding and flanking intronic regions in 136 sporadic pituitary adenomas using temporal temperature gradient gel electrophoresis (TTGE).
- Sequencing of identified aberrant DNA bands to detect mutations.
- Immunoblotting analysis of menin expression in 11 tumor samples and non-neoplastic adenohypophysis.
Main Results:
- Five novel somatic MEN1 mutations were identified, including missense, deletion, and intronic mutations.
- No significant association was found between identified MEN1 mutations and sporadic pituitary adenomas.
- Menin protein was upregulated in all examined adenomas, contradicting the hypothesis of menin downregulation.
Conclusions:
- MEN1 gene mutations do not appear to play a significant role in the pathogenesis of sporadic pituitary adenomas.
- Menin downregulation is unlikely to be a key mechanism in the development of these tumors.
- The findings suggest alternative pathways are involved in sporadic pituitary adenoma formation.