Genomic Characterization and Prognostic Impact of the TP53-Y220C Mutation Across Solid Tumors in Real-World Data

Background
TP53 is the most frequently mutated tumor suppressor gene in solid tumors. Targeted therapies designed to restore the function of mutated or inactive TP53 are in development. In particular, there has been substantial interest in TP53-Y220C as a targetable hotspot mutation. In this study, we used real-world data to map the clinico-genomic landscape of patients with TP53-Y220C across solid tumors.

Methods
We performed a retrospective analysis on 200,391 de-identified patient samples with solid tumors using the Tempus Lens Platform. Tumors were classified as TP53 wild-type (WT; no pathogenic TP53 variants) or Y220C. We assessed Y220C prevalence, driver co-alterations, and HRD status. Real-world overall survival (rwOS) was defined as time from sample collection to death or last known follow-up. Hazard ratios (HR) were estimated via a multivariate Cox proportional model adjusted for age, sex, race, ECOG performance status, stage, and cancer type.

Results
TP53-Y220C was detected in 0.9% of tumors (1,778), with the highest prevalence in ovarian cancer (3%). Compared to TP53-WT, patients with Y220C were older (66 vs. 64 years), and less frequently stage IV (68% vs. 74%) (all p<0.001). Across solid tumors, the most frequent co-alterations were KRAS (21%) and CDKN2A (23%); nearly all Y220C pancreatic tumors co-harbored KRAS (96%), and 80% of colorectal cancers had APC alterations. Among ovarian Y220C cases, 59% were HRD-positive. Tumors with Y220C had shorter rwOS than TP53-WT (HR 1.26; 95% CI 1.17–1.36; p<0.001). Concurrent Y220C with CDKN2A or KRAS alterations resulted in shorter rwOS compared to Y220C alone (HR: 1.41; 95% CI 1.15–1.73; p<0.001 and HR: 1.15; 95% CI 0.87–1.51; p=0.30, respectively). By cancer type, significantly worse rwOS was seen in ovarian (HR 1.36; 1.07–1.73; p=0.013), uterine (HR 2.13; 1.52–2.99; p<0.001), and pancreatic (HR 1.42; 1.17–1.72; p<0.001) cancers, while colorectal and lung cancers trended toward improved rwOS. No rwOS difference was seen in high-grade serous ovarian cancer.

Conclusions
Compared to TP53-WT, TP53-Y220C defines a genomically and clinically distinct pan-cancer subgroup. Real-world multimodal datasets can help inform clinical trial design as TP53-targeting strategies are developed.