Maureen Murphy (The Wistar Institute), Jessica Leung (The Wistar Institute), Julia Leu (University of Pennsylvania), Alexandra Indeglia (The Wistar Institute), Nicole Clarke (The Wistar Institute), Toshitha Kannan (The Wistar Institute), Nicole Kirven (The Wistar Institute), Thibaut Barnoud (The Wistar Institute), Andrew Kossenkov (The Wistar Institute), Donna George (University of Pennsylvania)
Mutational inactivation of TP53 occurs commonly in cancer. In addition to mutation, there are over two hundred germline genetic variants in the TP53 coding region; some of these produce partially functional (hypomorphic) protein. Presently the impact of hypomorphic p53 variants on cancer risk is unknown. Also missing is a test to distinguish hypomorphs from benign variants and/or wild type p53. We report that two African-centric hypomorphs of TP53, Pro47Ser and Tyr107His, share common activities. Specifically, these variants share an increased propensity to misfold into a conformation specific for mutant, misfolded p53, and to activate NF-kB. These hypomorphs also increase migration and invasion, and share common impact on metabolism and drug resistance. RNA sequencing data reveals a gene signature that is predictive of hypomorphic p53 from wild type or benign variants. These data support a role for misfolding of hypomorphic p53 on cancer risk and the efficacy of cancer therapy. They also suggest that a predictive gene signature could have profound impact on the over 4 million individuals in the United States with germline coding region variants of p53.
