GSE209837
Common activities and predictive gene signature identified for genetic hypomorphs of TP53
Mutational inactivation of TP53 is a common event in cancer.  Germline mutations in TP53 that inactivate this protein also occur in Li Fraumeni syndrome, which predisposes to early-onset cancer.  In addition, there are dozens of other germline variants in TP53 that do not completely inactivate the function of this protein.  In many cases studies have shown strong support for an impact of these lesser-functioning hypomorphs with increased cancer risk in humans and mouse models; however, the majority of these hypomorphs have yet to be categorized as pathogenic in clinical genetics databases.  There is thus need for a functional assay to distinguish lesser-functioning hypomorphic p53 variants from wild type p53, or benign, fully-functional, variants.  We report the surprising finding that two different African-centric genetic hypomorphs of p53, which occur in distinct functional domains of the protein, share common activities.  We show that the Pro47Ser variant in the transactivation domain and the Tyr107His variant in the DNA binding domain both share increased propensity to misfold into a conformation specific for mutant p53.  Moreover, cells and tissues with these variants show increased NF-?B activity.  We have identified a common gene signature from unstressed lymphocyte cell lines that is shared between these two, and other, genetic missense hypomorphs of TP53.  We show that this gene signature successfully distinguishes wild type p53 and a benign p53 variant from lesser-functioning hypomorphic variants.  These findings should allow us to better understand how hypomorphic variants contribute to cancer risk, and to better inform cancer risk in hypomorph carriers. Overall design: RNA-seq of samples with wild type or hypomorphic p53