Abstract
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.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call