TP53 Variant Clusters Stratify the Li-Fraumeni Spectrum and Reveal an Osteosarcoma-Prone Subgroup

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 dataset, we performed an unsupervised cluster analysis that revealed five TP53 variant clusters with unique structural and functional consequences. Using discovery and validation cohorts, classifying variant carriers according to these clusters stratified cancer onset and survival, 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported in part by a Terry Fox New Frontiers Program Project grant from the Terry Fox Research Institute (#1084). C.P.K. has been supported by the BMBF ADDRess (01GM2205A) and by the Deutsche Kinderkrebsstiftung (DKS2021.25). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of the Childrens Hospital of Philadelphia and the Perelman School of Medicine gave ethical approval for this work. Ethics committee of Hannover Medical School gave ethical approval for this work. Ethics committee of The Hospital for Sick Children gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript