Next-Generation Sequencing Reveals a Diagnostic and Prognostic Role of the TP53 R273C Mutation in Lower-Grade, IDH-Mutant Astrocytomas

The current WHO grading of central nervous system tumors relies exclusively on histopathological criteria for diagnosing lower-grade, IDH-mutant astrocytomas (LGIMAs), overlooking genetic features. The <i>TP53</i> R273C mutation, frequently observed in brain tumors, may influence LGIMA biology and aggressiveness. We analyzed 14 <i>TP53</i>-mutant LGIMAs using NGS. Five tumors (33.3%) carried the R273C mutation; these were mostly of grade 2 and all from female patients. Ki-67 levels in R273C-mutant tumors were higher compared with those in other <i>TP53</i>-mutant grade 2 tumors but lower than those in grade 3 tumors, which may suggest that R273C defines a more aggressive grade 2 profile. This mutation was linked to loss of the wild-type allele, supporting a loss-of-function mechanism. Its frequency was found to be potentially higher in women, and this sex-based difference reached statistical significance when incorporating TCGA LGIMA data. Overall, the R273C mutation, although mechanistically unclear, is more prevalent than other <i>TP53</i> variants and defines a distinct biological subset of LGIMAs, marked by increased Ki-67 and female predominance. Incorporating <i>TP53</i> and broader genetic profiling via NGS could improve our understanding of LGIMAs and support a refined classification system, enhancing diagnostic and prognostic accuracy.