Abstract 844: Germline TP53 missense mutations at codon338 confer adult-onset cancer risk through weakened p53 protein oligomeric stability that impairs its tumor suppressive mechanisms

Abstract

Abstract Pathogenic TP53 germline variants predispose carriers to a high lifelong cancer risk in Li-Fraumeni syndrome (LFS). LFS presents as a broad phenotypic spectrum with highly variable age-of-onset and tumor types. The mechanisms leading to these phenotypic differences remain largely unknown, and many less frequent variants are not clinically defined as pathogenic or benign. Two missense mutations in the tetramerization domain of the p53 protein, F338S and F338C, have recently been of clinical interest; however, they are currently classified as variants of uncertain significance. Normally, p53 assembles as a tetrameric complex to bind DNA and transcriptionally regulate the expression of target genes involved in the cellular response to stress, acting as a crucial barrier to malignant transformation. Alterations to p53 structure can therefore lead to malfunction and ultimately tumor formation. Our structural analysis of the tetramerization domain demonstrates that F338S and F338C have significantly lower thermal stability compared to the wildtype protein. Furthermore, our functional assessments of apoptosis and the suppression of colony formation indicate that both variants operate with reduced tumor suppressor activity, although they maintain near wildtype functionality. We anticipate that our results will help to better understand why these mutations cause a history of predominantly adult-onset cancers in the affected families and could justify refining surveillance measures for these individuals. Citation Format: Nicholas W. Fischer, Jaime Turk, Noel Ong, Shili Duan, Lilia Kaustov, Christian Kratz, Kristian Pajtler, Raymond Kim, Cheryl Arrowsmith, David Malkin. Germline TP53 missense mutations at codon338 confer adult-onset cancer risk through weakened p53 protein oligomeric stability that impairs its tumor suppressive mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 844.