Abstract A005 <i>TP53</i> variant clusters stratify the Li-Fraumeni spectrum and reveal an osteosarcoma-prone subgroup

Abstract Li-Fraumeni syndrome (LFS) has recently been redefined as a ‘spectrum’ cancer predisposition disorder to reflect its broad phenotypic heterogeneity. The wide functional gradient associated with different TP53 variants is thought to contribute to LFS heterogeneity, although it is still poorly understood and there is an unmet clinical need for risk stratification strategies. Leveraging p53 mutagenesis datasets, we performed an unsupervised cluster analysis that revealed five TP53 variant clusters with unique structural and functional consequences. Classifying variant carriers according to these clusters stratified cancer onset and survival using discovery and validation cohorts, and exposed important clinical characteristics to consider for patient management. In particular, we identified a subgroup of monomeric TP53 variant carriers prone to osteosarcoma, along with a cluster associated with less “LFS-like” phenotypes enriched in carriers with no history of cancer. Our classification of TP53 variants demonstrates the existence of a wide TP53-heritable cancer susceptibility spectrum and provides a new framework to delineate carriers toward personalized patient care. Citation Format: Nicholas W. Fischer, Brianne Laverty, Noa Alon, Emilie Montellier, Pierre Hainaut, Kara N. Maxwell, Christian P. Kratz, David Malkin. TP53 variant clusters stratify the Li-Fraumeni spectrum and reveal an osteosarcoma-prone subgroup [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A005.