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Published on: August 25, 2021
Human pheochromocytomas show reduced p27Kip1 expression that is not associated with somatic gene mutations and rarely
Natalia S Pellegata1, Leticia Quintanilla-Martinez, Gisela Keller
1Institute of Pathology, GSF-National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. natalia.pellegata@gsf.de
Abstract:
Pheochromocytomas are neuroendocrine tumors arising in the neural crest-derived chromaffin cells of the adrenal gland or in extra-adrenal sympathetic ganglia (paragangliomas). In a rat model of multiple endocrine neoplasia (MEN), absence of functional p27Kip1 protein predisposes to pheochromocytoma and paraganglioma development. As no data is available regarding the involvement of p27Kip1 in human pheochromocytoma and/or paraganglioma, we set out to determine the expression pattern of p27Kip1 in those tumor types. A panel of 25 pheochromocytomas and 23 paragangliomas was collected. Two pheochromocytomas were from MEN2 patients. The paragangliomas included 15 tumors that developed at the carotid bifurcation, three in the jugulo-tympanic area, and five at other sites. Except for the MEN2 cases, all others were apparently sporadic. Immunohistochemistry for p27Kip1 and the proliferation marker Ki67 was performed. We found that p27Kip1 expression is reduced/lost in 56% of pheochromocytomas, but only in 18.1% of paragangliomas. Downregulation of p27Kip1 was not associated with increased proliferation. Cases showing reduced/lost p27Kip1 expression were screened for the presence of somatic mutations in CDKN1B (p27Kip1) and for allelic imbalance at the p27Kip1 locus. Three cases had allelic imbalance but none had mutations. In conclusion, pheochromocytomas display extreme reduction/loss of p27Kip1 expression at high frequency.
Insights
Pheochromocytomas frequently show reduced or lost p27Kip1 protein expression, unlike paragangliomas. This finding is crucial for understanding neuroendocrine tumor development and potential therapeutic targets.
Area of Science:
- Neuroendocrinology
- Oncology
- Molecular Biology
Background:
- Pheochromocytomas and paragangliomas are neuroendocrine tumors originating from neural crest cells.
- A rat model suggests p27Kip1 protein absence contributes to tumor development.
- Limited data exists on p27Kip1's role in human pheochromocytoma and paraganglioma.
Purpose of the Study:
- To investigate the expression pattern of p27Kip1 in human pheochromocytomas and paragangliomas.
- To determine if p27Kip1 alterations correlate with tumor type or proliferation.
- To screen for mutations and allelic imbalance in the CDKN1B gene.
Main Methods:
- Immunohistochemistry was used to assess p27Kip1 and Ki67 expression in 25 pheochromocytomas and 23 paragangliomas.
- Genetic analysis, including mutation screening and allelic imbalance detection, was performed on cases with reduced p27Kip1.
- Tumor samples included sporadic and multiple endocrine neoplasia (MEN2) cases.
Main Results:
- Reduced or lost p27Kip1 expression was observed in 56% of pheochromocytomas.
- Only 18.1% of paragangliomas showed reduced or lost p27Kip1 expression.
- No significant association was found between p27Kip1 downregulation and increased proliferation; mutations in CDKN1B were not detected, though allelic imbalance was present in three cases.
Conclusions:
- Pheochromocytomas exhibit a high frequency of p27Kip1 expression loss.
- The findings highlight a potential difference in p27Kip1 involvement between pheochromocytomas and paragangliomas.
- Further research is needed to elucidate the mechanisms behind p27Kip1 downregulation in pheochromocytomas.
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