Abstract Whole-genome doubling (WGD) is a frequent yet poorly understood genomic event linked to adverse clinical outcomes. Multiple distinct mechanisms can lead to tetraploidization and aneuploidy, including defects in the mitotic checkpoint, chromosome cohesion, and disruptions of microtubules, spindle assembly, or centromere function. In addition, cell-cell fusion events can also result in polyploidization. Polyploid cells often exhibit chromosomal instability, which contributes to increased intratumoral heterogeneity and accelerates the evolution of the cancer genome. Although chromosomal instability and the presence of tetraploid or hyperdiploid cancer cells have been linked to treatment resistance and enhanced phenotypic diversity, the molecular mechanisms driving these associations remain poorly understood. We began by assessing the frequency of WGD in breast cancer across tumor subtypes and stages of disease progression. To do this, we performed WGD calling or reanalyzed publicly available genomic sequencing datasets with annotated WGD status. Analysis of three datasets revealed that WGD occurs more frequently in HER2+ and triple-negative breast cancers (TNBC) compared to hormone receptor-positive tumors. Furthermore, WGD frequency was consistently higher in distant metastases than in primary tumors. We then established through homofusion several murine mammary tumor models of WGD of TNBC to investigate how WGD drives tumor evolution. We observed that WGD increases transcriptomic and epigenetic heterogeneity and identified the survivin inhibitor YM155 as a selective suppressor of WGD+ tumors. Importantly, WGD promoted immune evasion by enabling escape from CD8+ T cell-mediated immune responses, rendering WGD+ tumors more sensitive to anti-PD-L1 therapy. Through single-cell profiling, we found that WGD+ cancer cells exhibit impaired antigen presentation, driven in part by a reduced response to IFN-γ and epigenetic silencing of MHC class I transcriptional regulators via the PRC2 complex. Treatment with a PRC2 inhibitor preferentially inhibited WGD+ tumor growth, restored antigen presentation, and enhanced CD8+ T cell infiltration. These findings suggest that combined inhibition of PRC2 and PD-1 represents a promising therapeutic approach for WGD+ breast cancers. Keywords: Whole genome doubling, Breast Cancer, single cell profiling, immune escape Citation Format: P. Foidart, Z. Li, X. Can, M. Seehawer, E. Rojas-Jimenez, P. Baldominos, J. Nishida, T. Bui, B. Diciaccio, S. Parvin, M. Goyette, P. Yan, X. Qiu, R. Li, Y. Jiang, Y. Xie, X. Huang, L. E. Stevens, P. Cejas, L. Mangiante, C. I. Sotomayor Vivas, K. Houlahan, T. Scales, I. S. Harris, C. Curtis, A. G. Letai, H. W. Long, J. Agudo, K. Polyak. Whole-genome doubling promotes immune evasion in TNBC by epigenetically silencing antigen presentation pathways through PRC2 activity abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-27.
Foidart et al. (Tue,) studied this question.