Abstract 5051: Evolutionary characterization and refinement of copy-number high endometrial carcinoma
Authors: Kramer Claire J. , Ruano Dina , Hawari Aliah , Blanc-Durand Felix , de Kroon Cor D. , Kroep Judith R. , Ortoft Gitte , Hogdall Estrid , Leary Alexandra , Creutzberg Carien L. , Vreeswijk Maaike P. , Horeweg Nanda , Church David N. , Wedge David C. , Bosse Tjalling 
Published: March 2024

Abstract
Copy-number (CN)-high endometrial carcinoma (EC) is characterized by abundant CN-alterations, thought to be driven by TP53 aberrations, and is the subgroup with the poorest prognosis. CN-high EC exhibit substantial heterogeneity in histotypes, molecular markers, and mutational profiles. Here, we aimed to refine this subgroup by assessing the evolution and identifying CN-signatures (Drews et al. Nature) to establish CN-clusters. We used whole-genome sequencing (WGS;100X) data from 146 CN-high cases from Genomics England (GeL) as discovery cohort. We then performed shallow WGS (sWGS;0.1X) of FFPE tumor DNA of n=307 CN-high EC from (non-)trial cohorts. Timing of canonical driver mutations by MutationTimer in CN-high GeL revealed that TP53 mutations were: (i) not ubiquitous and (ii) not consistently identified as early clonal events (Table), challenging conventional belief that TP53 inactivation is necessary for initiation of CN-high EC. Evolutionary analyses (Plackett-Luce) are ongoing to identify carcinogenesis trajectories and assess how driver mutations other than TP53 influence CN-phenotypes. Unsupervised clustering of 307 EC by CN-signatures identified five clusters (E1: 19%; E2: 2%; E3; 20%; E4: 19%; E5: 40%), characterized by CN-signatures linked to biological phenomena. Clusters E1/E4 reflect homologous recombination deficiency (CX3), while cluster E5 seems driven by chromosomal missegregation (CX1). Notably, there was no one-to-one relationship between CN-clusters and histotypes, suggesting CN-evolution is independent of morphology. In conclusion, we have identified TP53-dependent and -independent pathways in CN-high EC evolution. Potentially clinically relevant CN-clusters were identified using cost-effective sWGS. sWGS of additional n=475 CN-high EC are ongoing. Furthermore, we will analyze in-depth clinicopathological relationships of clusters, including prognosis/prediction, using PORTEC trials prior to the meeting.
Table. Timing of canonical driver mutations in CN-high EC Clonal - early Clonal - late Subclonal Clonal - NA Total 1. TP53 87 (67%) 4 (3%) 3 (2%) 36 (28%) 130 (100%) 2. PIK3CA 42 (76%) 1 (2%) 1 (2%) 11 (20%) 55 (100%) 3. PPP2R1A 18 (47%) 1 (3%) 2 (5%) 17 (45%) 38 (100%) 4. PTEN 17 (59%) 1 (3%) 2 (7%) 9 (31%) 29 (100%) 5. PIK3R1 11 (46%) 0 (0%) 3 (13%) 10 (42%) 24 (100%) 6. FBXW7 14 (61%) 0 (0%) 0 (0%) 9 (39%) 23 (100%) 7. KRAS 9 (64%) 0 (0%) 2 (14%) 3 (21%) 14 (100%) Abbreviation: NA, timing not applicable.
Citation Format: Claire J. Kramer, Dina Ruano, Aliah Hawari, Felix Blanc-Durand, Cor D. de Kroon, Judith R. Kroep, Gitte Ortoft, Estrid Hogdall, Alexandra Leary, Carien L. Creutzberg, Maaike P. Vreeswijk, Nanda Horeweg, David N. Church, David C. Wedge, Tjalling Bosse. Evolutionary characterization and refinement of copy-number high endometrial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5051.