Abstract 7458: Germline-p53-mutant adrenocortical carcinoma is a possible candidate for the novel use of arsenic trioxide as a first targeted anticancer therapy for Li-Fraumeni syndrome

Abstract Background: Li-Fraumeni Syndrome (LFS) is a cancer predisposition disorder associated with germline mutations in the tumor suppressor gene TP53, which encodes the protein p53. Despite a near-guarantee for individuals with LFS to develop cancer during their lifetime, there are still no specific antitumor therapies for LFS. As a possible approach to address this unmet clinical need, FDA-approved anticancer agent arsenic trioxide (ATO) has recently been shown to rescue a wide spectrum of p53 mutants back to wild-type structure and function. However, ATO-rescuable p53 mutants have not been examined in a germline context to date, preventing an understanding in the field of ATO’s capacity to serve as a first targeted therapy for LFS. Methods: To address this gap, we integrated published research data on 103 ATO-rescuable p53 mutants with public clinical and mutational data on 842 individuals with germline-p53-mutant cancers in the TP53 Database and 12, 793 individuals with somatic-p53-mutant cancers in the cBioPortal database. Ensuing in silico analyses included p53 mutant and cancer prevalence calculations, statistical tests of proportions and associations, unsupervised cluster analysis, and Cox proportional hazards modeling. Results: ATO-rescuable p53 mutants overall were significantly enriched in germline-p53-mutant cancers compared to somatic-p53-mutant cancers. In both cohorts, ATO-rescuable p53 mutants overall were significantly associated with damaged function, dominant-negative effects, and loss of function, but were not significantly linked with sex or earlier ages of diagnosis. At the mutational level, ATO-rescuable p53M133T, p53P152L, p53R158H, and (also hotspot mutant) p53G245S were significantly enriched in germline-p53-mutant cancers compared to somatic-p53-mutant cancers. Notably, ATO-rescuable p53R175H and p53R282W, both also hotspot mutants, were equally highly prevalent in both cohorts. Within germline-p53-mutant cancers, ATO-rescuable p53 mutants were significantly enriched in adrenocortical carcinoma (ACC) compared to the full germline cohort and to other cancers frequently diagnosed in LFS. Unsupervised cluster analysis identified a cluster of three p53 mutants, two of which were ATO-rescuable (p53P152L and p53R158H), specifically associated with germline-p53-mutant ACC. Cox proportional hazards modeling subsequently revealed this cluster was significantly associated with a higher risk for individuals to develop ACC independent of other p53 mutants, sex, type of p53 mutant, and p53 domain of residues affected. Conclusions: This work provides the first insights in the field on potential germline p53 mutant and cancer candidates for the novel use of ATO as a first targeted antitumor therapy for individuals with LFS. Citation Format: Neha Wali, Richard P. Owen, Curtis C. Harris, Xin Lu. Germline-p53-mutant adrenocortical carcinoma is a possible candidate for the novel use of arsenic trioxide as a first targeted anticancer therapy for Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7458.