Role of a p53 polymorphism in the development of nonfunctional pituitary adenomas

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.

The Role of Single-Nucleotide Polymorphisms in Pituitary Adenomas Tumorigenesis

“…As such, these present almost a decade earlier with symptomatic NFPAs. Interestingly, when wild-type cultured NFPA cells were transfected with the rs1042522 G variant, a concomitant decrease in p21 was noted along with increased cellular proliferation, suggesting that this TP53 SNP influenced NFPA growth [28].…”

“…Yagnik et al (2017) investigated the role of p53 polymorphisms in the development of NFPAs. Their study 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 around 80% of NFPAs [28]. The tumor suppressor protein, p53, functions to conserve genomic stability and, in cases of irreparable damage, can guide cells towards cell cycle arrest via interaction with p21 mediator proteins or towards apoptosis [29].…”

Interactions among variants in P53 apoptotic pathway genes are associated with neurologic deterioration and functional outcome after acute ischemic stroke

“…Two general pathways of apoptosis are triggered after cerebral ischemia, that is, intrinsic pathway (originating from mitochondrial release of cytochrome c) and the extrinsic pathway (originating from the activation of cell surface death receptors) (Broughton et al, 2009). Genetic polymorphisms of cell‐cycle regulating genes may affect the DNA damage (Yagnik, Jahangiri, Chen, Wagner, & Aghi, 2017). When cells are damaged, cell division will stop in G1 phase of mitosis (Duan et al, 2017).…”

Biomarker Discovery for Immunotherapy of Pituitary Adenomas: Enhanced Robustness and Prediction Ability by Modern Computational Tools

“…Till now, chemotherapy and kinase inhibitors have emerged as the most promising candidates with temozolomide and lapatinib in clinical developments [21,26,33], but they suffer from severe myelotoxicity, mental disturbances or cardiac dysrhythmia that can substantially affect the approval processes of these clinical candidates [34,35,36]. So far, no effective drug has been developed for treating non-functional pituitary tumors, and the removal of cancerous cells directly from the pituitary is still under experimental investigation [37,38,39]. It is thus crucial to discover a new strategy for PA treatment.…”