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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Role of a p53 polymorphism in the development of nonfunctional pituitary adenomas
Garima Yagnik1, Arman Jahangiri1, Rebecca Chen1
1University of California, San Francisco (UCSF) Department of Neurological Surgery and Brain Tumor Research Center, 1450 Third Street Room HD-465, San Francisco, CA 94158, USA.
Abstract:
Non-functional pituitary adenomas (NFPAs) are among the commonest intracranial neoplasms. While histologically benign, NFPAs sometimes become large enough to limit therapeutic options and reduce quality of life. Investigations of the molecular etiology of NFPAs have failed to identify prevalent genetic changes and, while a role for p53 has been suggested, TP53 gene alterations have yet to be described in NFPAs. We found that the polymorphism rs1042522:C > G in codon 72 of exon 4 of the TP53 gene, whose C variant produces a proline and is more common in most ethnicities, has a G variant producing an arginine in 79.8% of NFPAs (n = 42; p < 1.411 × 10-18 vs. 1000 Genomes database), causing patients to present a decade earlier with symptomatic NFPAs. In cultured NFPA cells, transfection with the rs1042522 G variant versus the C variant reduced expression of cell arrest gene p21 and increased proliferation. These findings suggest that this TP53 polymorphism influences NFPA growth.
Insights
A common TP53 gene variant (rs1042522 G) is prevalent in non-functional pituitary adenomas (NFPAs), leading to earlier symptom onset. This variant promotes NFPA cell growth by reducing cell cycle arrest gene p21 expression.
Area of Science:
- Neuro-oncology
- Genetics
- Molecular Biology
Background:
- Non-functional pituitary adenomas (NFPAs) are common brain tumors.
- The molecular causes of NFPAs are not well understood.
- TP53 gene alterations have not been previously identified in NFPAs.
Purpose of the Study:
- To investigate the role of TP53 gene variations in the development of NFPAs.
- To determine if specific TP53 polymorphisms are associated with NFPA characteristics, such as age of presentation and tumor growth.
Main Methods:
- Genotyping analysis of the TP53 gene polymorphism rs1042522 in NFPA patients.
- Comparison of allele frequencies with the 1000 Genomes database.
- In vitro studies using cultured NFPA cells to assess the functional impact of different TP53 variants on gene expression and cell proliferation.
Main Results:
- The G variant of TP53 polymorphism rs1042522 was found in 79.8% of NFPA patients, significantly higher than in the general population.
- Patients with the G variant presented with symptomatic NFPAs approximately a decade earlier.
- In vitro, the G variant reduced p21 expression and increased cell proliferation compared to the C variant.
Conclusions:
- The TP53 gene polymorphism rs1042522 significantly influences NFPA development and progression.
- The G variant may promote NFPA growth and lead to earlier clinical manifestation.
- This finding sheds light on the molecular mechanisms underlying NFPA tumorigenesis.
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