Abstract 3403: The landscape of TP53 Y220C mutations in cancer
Authors: Alison M. Schram, Fatema Nagib, Mara Rao, Rogelio Velasco, Michael Gormally, Alexandra Waksmundzki, Henry Walch, Michael Berger, Nikolaus Schultz, Mark Donoghue, Walid Chatila
Journal: Cancer Research (2025)

Abstract Background: TP53 encodes the critical tumor suppressor p53 and is the most commonly mutated gene in cancer. The TP53 Y220C hotspot mutation occurs in approximately 1% of solid tumors, reduces thermal stability of TP53, and impairs its DNA binding. TP53 Y220C creates a unique conformational change that is amenable to small molecules that can restore TP53 function. Several TP53 Y220C reactivators are in development. Despite emerging evidence that TP53 Y220C is a therapeutic target, the clinicopathologic features of patients with these tumors remain poorly understood. We describe the landscape of TP53 Y220C solid tumors at Memorial Sloan Kettering Cancer Center (MSK). Methods: This retrospective study included patients with TP53 Y220C solid tumors at MSK from July 2014 to March 2024. Patients were identified using paired tumor-normal next-generation sequencing (NGS) with MSK-IMPACT, a hybridization capture-based NGS assay that detects mutations, copy number alterations, and select structural rearrangements. Clinicopathologic data including sex, age and stage at diagnosis, race, and cancer type were automatically extracted from the medical record. Allele-specific copy number analysis was performed using FACETS, which infers purity and ploidy corrected integer DNA copy number calls from sequencing data. Genomic characteristics of TP53 Y220C solid tumors were compared to those with other TP53 missense mutations, truncating mutations, and complex alterations involving TP53, in addition to TP53 wild-type tumors. Results: 498 patients were identified with TP53 Y220C-mutated solid tumors. The majority were female (67%), White (71%), never smokers (52%), with a median age of 63 years-old (range 16-90, n=479). Approximately half (56%) had stage I-III disease at diagnosis, 33% stage IV, 11% unknown. The most common tumor types were ovarian (22%), pancreatic (11%), breast (11%), and non-small cell lung cancer (10%). TP53 Y220C prevalence was highest in high-grade serous ovarian cancer (4.5%). TP53 Y220C rarely co-occurred with other TP53 mutations (0.07%). The co-mutational profile, tumor mutational burden, copy number profile, and fraction of genome altered of TP53 Y220C-mutated tumors was similar to tumors with p53 non-Y220C mutations. Whole genome doubling (WGD) occurred in approximately half of TP53 altered cases, with similar frequencies for TP53 Y220C and TP53 non-Y220C mutated cancer. The frequency of WGD was higher in the altered groups compared to the TP53 wild-type group. Mutations were predominantly clonal, with subclonal alterations found in only 0.7% of cases. Conclusion: TP53 Y220C is a newly described clinically actionable target found across solid tumors at low frequency. The genomic features of TP53 Y220C-mutated cancers are similar to TP53 non-Y220C mutated cancers. Research is ongoing to determine the natural history of TP53 Y220C mutated cancers and whether this biomarker has unique predictive or prognostic implications. Citation Format: Alison M. Schram, Fatema Nagib, Mara Rao, Rogelio Velasco, Michael Gormally, Alexandra Waksmundzki, Henry Walch, Michael Berger, Nikolaus Schultz, Mark Donoghue, Walid Chatila. The landscape of TP53 Y220C mutations in cancer [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 3403.