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

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.