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In cancer, missense mutations in the DNA-binding domain of TP53 are common. They abrogate canonical p53 activity and frequently confer gain-of-oncogenic function (GOF) through localization of transcriptionally active mutant p53 to noncanonical genes. We found that several recurring p53 mutations exhibit a sex difference in frequency in patients with glioblastoma (GBM). In vitro and in vivo analysis of three mutations, p53R172H, p53Y202C, and p53Y217C, revealed unique interactions between cellular sex and p53 GOF mutations that determined each mutation's ability to transform male versus female primary mouse astrocytes. These phenotypic differences were correlated with sex- and p53 mutation–specific patterns of genomic localization to the transcriptional start sites of upregulated genes belonging to core cancer pathways. The promoter regions of these genes exhibited a sex difference in enrichment for different transcription factor DNA-binding motifs. Together, our data establish a novel mechanism for sex-specific mutant p53 GOF activity in GBM with implications for all cancer. Significance: Sex differences in cancer, including glioblastoma, have been observed in both incidence and outcome. We reveal that TP53, the most commonly mutated gene in cancer, contributes to sex differences through differential GOF activity. This discovery has critical implications for our understanding of p53 mutations and the importance of sex as a biological variable.

Sex- and Mutation-Specific p53 Gain-of-Function Activity in Gliomagenesis