Abstract PR08: African-centric p53 hypomorphs play significant roles in cancer risk and efficacy of therapy

The p53 tumor suppressor gene plays a central role in human cancer. In addition to mutation, there are genetic coding region variants of p53 that exist in different ethnic groups. In some cases, these variants have incomplete or impaired function and confer increased cancer risk. We call such variants ‘hypomorphs’. Two p53 hypomorphs exist in populations of African descent: P47S and Y107H. Our research on the P47S hypomorph of p53 revealed that this variant confers increased risk for cancer in humans and in mouse models (Jennis, Genes Dev 2016; Murphy, NPJ Breast Cancer 2017). We find that P47S protein is selectively impaired for the ability to confer sensitivity to ferroptosis (Leu, PNAS 2019); consequently, we find that human and mouse cells with this variant accumulate iron in certain tissues, and that the P47S variant is associated with iron overload in African Americans (Singh, Nat Comm 2020). We find that tumor cells containing the P47S variant are resistant to most genotoxic chemotherapies, but we have discovered that P47S tumor cells are markedly more sensitive to other therapies, including cisplatin and BRD2/4 inhibitors (Barnoud, Can Res 2018). Our current focus is on another African-centric p53 hypomorph, Y107H. We show that this variant is impaired for p53-mediated apoptosis, and is associated with cancer risk in a mouse model. We also show that Y107H is impaired for the transactivation of only a dozen p53 target genes. Notably, half of these genes are known tumor suppressor genes. Our biophysical and NMR structure of the Y107H protein explains the mechanistic basis for the impaired function of this hypomorph. Our analysis of the P47S and Y107H hypomorphs of p53 has significant potential to understand cancer risk and improve cancer therapy in populations of African descent.

Citation Format: Tim Barnoud, Jessica Leung, Keerthana Gnanapradeepan, Lei Ke, John Karanicolas, Maureen E. Murphy. African-centric p53 hypomorphs play significant roles in cancer risk and efficacy of therapy [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR08.