Abstract 2677: Identifying and analyzing clinicopathological features of uterine endometrial endometrioid tumors discordant by p53 and copy number status.

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Abstract The Cancer Genome Atlas (TCGA) identified four molecular subtypes of endometrial carcinoma: POLE, high microsatellite instability (MSI-H), copy number-low and copy number-high. These classifications were eventually adopted into clinical practice in the form of ProMisE, a molecular classifier for endometrial cancers based on TCGA. While TCGA used hierarchical clustering to define copy-number high and low clusters, ProMisE utilizes TP53 mutation as a marker of the copy-number (CN) high and low subgroups. We have observed discordances between TP53 mutation call and copy-number status. We developed a method to redefine CN-high based on the presence of a single chromosomal arm-level deletion in a tumor. Arm-level copy number calls were generated by running the algorithm ASCETS (Arm-level Somatic Copy-number Events in Targeted Sequencing) on copy number segmentation data to give arm-level copy number calls. We validated this approach using molecular subtypes from both TCGA and CPTAC (Clinical Proteomic Tumor Analysis Consortium) data after taking out MMR-D/MSI-H and POLE patients, yielding accuracies of 0.823 and 0.865, respectively. Next, we applied this approach to a cohort of 446 endometrioid endometrial tumors profiled using a next-generation targeted sequencing panel (OncoPanel). After removing MSI-H/POLE tumors, we found 167 tumors concordant with regards to CN and TP53 mutation status (31 CN-high/TP53 mutant; 136 CN-low/TP53 wild-type), and 92 discordant tumors (84 CN-high/TP53 wild-type; 8 CN-low/TP53 mutant). Survival analysis stratified by TP53 mutation and copy number status called by arm-level deletion yields significantly worse overall survival for patients with both TP53 mutation and high copy number in both the CPTAC (p = 0.027) and OncoPanel (p < 0.0001) cohorts, but no significant difference in survival between TP53 WT/CN-high and TP53 WT/CN-low patients. Overall, we find that TP53 WT tumors have similar prognosis regardless of copy number status and have also found that CN-high/ TP53 mutant tumors may have significantly worse prognosis than CN-low/ TP53 mutant tumors (p = 0.036). Additional data will be used to confirm this. Citation Format: Sreekar B. Challa, Jessica D. St. Laurent, Zehra Ordulu, Alexander J. Neil, Melissa S. Gildenberg, Matthew L. Meyerson, Yvonne Y. Li, Andrew D. Cherniack, Elizabeth H. Stover. Identifying and analyzing clinicopathological features of uterine endometrial endometrioid tumors discordant by p53 and copy number status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2677.

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