Abstract
Tumor protein 53 (p53) regulates fundamental pathways of cellular growth and differentiation. Aberrant p53 expression in glioblastoma multiforme, a terminal brain cancer, has been associated with worse patient outcomes and decreased chemosensitivity. Therefore, correctly identifying p53 status in glioblastoma is of great clinical significance. p53 immunohistochemistry is used to detect pathological presence of the TP53 gene product. Here, we examined the relationship between p53 immunoreactivity and TP53 mutation status by DNA Sanger sequencing in adult glioblastoma. Of 41 histologically confirmed samples, 27 (66%) were immunopositive for a p53 mutation via immunohistochemistry. Utilizing gene sequencing, we identified only eight samples (20%) with TP53 functional mutations and one sample with a silent mutation. Therefore, a ≥10% p53 immunohistochemistry threshold for predicting TP53 functional mutation status in glioma is insufficient. Implementing this ≥10% threshold, we demonstrated a remarkably low positive-predictive value (30%). Furthermore, the sensitivity and specificity with ≥10% p53 immunohistochemistry to predict TP53 functional mutation status were 100% and 42%, respectively. Our data suggests that unless reliable sequencing methodology is available for confirming TP53 status, raising the immunoreactivity threshold would increase positive and negative predictive values as well as the specificity without changing the sensitivity of the immunohistochemistry assay.
Highlights
We examined the relationship between p53 immunoreactivity and tumor protein 53 (TP53) mutation status by deoxyribonucleic acid (DNA) Sanger sequencing in adult glioblastoma
Tumor protein 53 (p53) is a nuclear phosphoprotein involved in fundamental pathways of cellular growth and differentiation, including induction of apoptosis, commencement of deoxyribonucleic acid (DNA) repair, and transient arrest of the cell cycle in the G1 phase. p53 executes most of these cellular processes as a transcription factor, binding to DNA and regulating gene expression. p53 regulation of the cell cycle occurs by activating transcription of the WAF1 gene [1]
Among the 41 glioma samples collected for our Carilion Glioma Bank (CGB), p53 IHC reports had values ranging from 0-90% for p53 positive nuclei
Summary
Tumor protein 53 (p53) is a nuclear phosphoprotein involved in fundamental pathways of cellular growth and differentiation, including induction of apoptosis, commencement of deoxyribonucleic acid (DNA) repair, and transient arrest of the cell cycle in the G1 phase. p53 executes most of these cellular processes as a transcription factor, binding to DNA and regulating gene expression. p53 regulation of the cell cycle occurs by activating transcription of the WAF1 gene [1]. P53 regulation of the cell cycle occurs by activating transcription of the WAF1 gene [1]. The p21 protein is the translated product of WAF1 and functions to inhibit www.oncotarget.com cyclin-dependent kinases. This regulation causes the cell cycle to arrest in the G1 phase. Due to its prominent role in cell cycle regulation, p53 has numerous mechanisms to restrict uncontrolled cell division from occurring. The activity of this protein is predominantly regulated at the post-translational level. P14ARF, encoded by the cyclin-dependent kinase inhibitor 2A (CDK2NA) gene, binds and inhibits MDM2 [3]. Molecular interactions between p53, MDM2, and p14ARF fastidiously regulate the balance between the synthesis and turnover of p53, and control the progression of the cell cycle
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