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TP53 is considered the most frequently mutated gene in human cancers. This molecular abnormality is identified in 36–60% of gliomas in adults, and is particularly frequent in DA (11–63% of cases), AA (25–70% of cases), pGBM (28–35% of cases) and sGBM (50–65% of cases) [13, 22, 31, 36, 37, 49, 50]. AA demonstrates the highest prevalence of this abnormality [51]. In cases of adult LGG younger age of the patient may be associated with greater probability of TP53 mutation [8].

Wild-type p53 plays an important role in regulation of the cell cycle, apoptosis, and cell differentiation. Inactivation of TP53 is usually (but not always) biallelic and most commonly occurs through LOH of chromosome 17p with mutation in the remaining allele [32, 49]. The effects of molecular alteration can be realized through loss of function, gain of function, or by a dominant-negative pattern [37, 49, 51]. Mutant p53 contributes to oncogenesis through multiple mechanisms, including inability to arrest the cell cycle in G1 phase to allow either the reparation of damaged DNA or induction of apoptosis in cells that have acquired deleterious mutations and increased genomic instability; it leads to uninhibited growth, immortalization and malignant transformation [13, 14, 51]. Evaluation of p53 status with IHC is a routine technique, since >90% of TP53 mutations are nonsense and result in the decreased degradation of protein oligomers [13]. It has been suggested that a 10–20% threshold for stained cell nuclei may be effectively used as a surrogate marker for TP53 mutations [8, 52]. Of note, perinecrotic tumor areas may show some degree of p53 immunopositivity, which results from associated hypoxia, thus should not be considered a true positive. Moreover, negative immunostaining does not necessarily indicate functional p53. Frameshift TP53 mutations make up 10–20% of cases in astrocytomas and result in truncated protein that will be neither upregulated nor detected by IHC [14]. Finally, beyond TP53 mutations there are also other mechanisms of functional alteration of p53 that are typical for GBM (but nearly absent in LGG); for example, these include activation of the negative regulator Mdm2 encoded by MDM2 (mouse double minute 2 homolog; located at 12q14.3-q15) and downregulation of the modulator p14ARF (alternate reading frame) encoded by CDKN2A [14, 37, 49].

Isolated TP53 mutations in gliomas are very rare [22]. Since this molecular abnormality typically indicates astrocytic differentiation, in mixed cohorts of diffusely infiltrating gliomas, particularly LGG, its presence is associated with shorter survival of patients [8, 22]. However, prognostic and predictive values of TP53 mutations in cases of astrocytomas of any WHO histopathological grade remain unclear [37, 50]. Review of 44 studies incorporating 3,627 patients and meta-analyses performed by Levidou et al. [53] indicated that p53 immunopositivity is not significantly associated with a risk of mortality, neither in the combined cohort of diffusely infiltrating astrocytomas of various WHO grades nor in a subgroup of GBM.