RT Journal Article
SR Electronic
T1 p53 mutations exhibit sex specific gain-of-function activity in gliomagenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.11.448124
DO 10.1101/2021.06.11.448124
A1 Nathan Rockwell
A1 Wei Yang
A1 Nicole Warrington
A1 Malachi Griffith
A1 Obi Griffith
A1 Christina Gurnett
A1 Barak Cohen
A1 Dustin Baldridge
A1 Joshua Rubin
YR 2021
UL http://biorxiv.org/content/early/2021/06/11/2021.06.11.448124.abstract
AB The tumor suppressor TP53 is the most frequently mutated gene in cancer. Most TP53 mutations are missense mutations in the DNA-binding domain, which in addition to loss of canonical p53 activity, frequently confer gain-of-function (GOF) aberrant transcriptional activity through mutant p53 localization to non-canonical genes. GOF phenotypes differ by mutation and cell identity and are reported to include increased proliferation, migration, metabolic reprogramming, and therapy resistance. We found that several recurring p53 mutations exhibit a sex-bias in patients with glioblastoma (GBM). In vitro and in vivo analysis of three mutations, p53R172H, p53Y202C, and p53Y217C revealed sex differences in each mutation’s ability to transform primary mouse astrocytes. p53R172H exhibited a far greater ability to transform female astrocytes than males, p53Y202C transformed both male and female astrocytes with a small male bias, and p53Y217C only exhibited GOF transformation effects in male astrocytes. These phenotypic differences reflect an interaction between sex and GOF mutation to drive unique gene expression patterns in cancer pathways. We found that mutant p53 exhibits sex and mutation specific aberrant genomic localization to the transcriptional start sites of upregulated genes, whose promoter regions were enriched for different sets of transcription factor DNA-binding motifs. Together, our data establish a novel paradigm for sex specific mutant p53 GOF activity in GBM with implications for all cancer.Competing Interest StatementThe authors have declared no competing interest.