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| Item Type: | Article |
|---|---|
| Title: | Ongoing genome doubling shapes evolvability and immunity in ovarian cancer |
| Creators Name: | McPherson, Andrew, Vázquez-García, Ignacio, Myers, Matthew A., Al-Rawi, Duaa H., Zatzman, Matthew, Weiner, Adam C., Freeman, Samuel, Mohibullah, Neeman, Satas, Gryte, Williams, Marc J., Ceglia, Nicholas, Norkūnaitė, Danguolė, Zhang, Allen W., Li, Jun, Lim, Jamie L.P., Wu, Michelle, Choi, Seongmin, Havasov, Eliyahu, Grewal, Diljot, Shi, Hongyu, Kim, Minsoo, Schwarz, Roland F., Kaufmann, Tom, Dinh, Khanh Ngoc, Uhlitz, Florian, Tran, Julie, Wu, Yushi, Patel, Ruchi, Ramakrishnan, Satish, Kim, DooA, Clarke, Justin, Green, Hunter, Ali, Emily, DiBona, Melody, Varice, Nancy, Kundra, Ritika, Broach, Vance, Gardner, Ginger J., Roche, Kara Long, Sonoda, Yukio, Zivanovic, Oliver, Kim, Sarah H., Grisham, Rachel N., Liu, Ying L, Viale, Agnes, Rusk, Nicole, Lakhman, Yulia, Ellenson, Lora H., Tavaré, Simon, Aparicio, Samuel, Chi, Dennis S., Aghajanian, Carol, Abu-Rustum, Nadeem R., Friedman, Claire F., Zamarin, Dmitriy, Weigelt, Britta, Bakhoum, Samuel F. and Shah, Sohrab P. |
| Abstract: | Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1,2,3,4,5,6. Here we examine the impact of WGD on somatic evolution and immune evasion at single-cell resolution in patient tumours. Using single-cell whole-genome sequencing, we analysed 70 high-grade serous ovarian cancer samples from 41 patients (30,260 tumour genomes) and observed near-ubiquitous evidence that WGD is an ongoing mutational process. WGD was associated with increased cell–cell diversity and higher rates of chromosomal missegregation and consequent micronucleation. We developed a mutation-based WGD timing method called doubleTime to delineate specific modes by which WGD can drive tumour evolution, including early fixation followed by considerable diversification, multiple parallel WGD events on a pre-existing background of copy-number diversity, and evolutionarily late WGD in small clones and individual cells. Furthermore, using matched single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signalling and cGAS-STING pathway activation result from ongoing chromosomal instability, but this is restricted to predominantly diploid tumours (WGD-low). By contrast, predominantly WGD tumours (WGD-high), despite increased missegregation, exhibited cell-cycle dysregulation, STING1 repression, and immunosuppressive phenotypic states. Together, these findings establish WGD as an ongoing mutational process that promotes evolvability and dysregulated immunity in high-grade serous ovarian cancer. |
| Keywords: | Chromosomal Instability, DNA Copy Number Variations, Human Genome, Membrane Proteins, Molecular Evolution, Mutation, Nucleotidyltransferases, Ovarian Neoplasms, Signal Transduction, Single-Cell Analysis, Whole Genome Sequencing |
| Source: | Nature |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Volume: | 644 |
| Number: | 8078 |
| Page Range: | 1078-1087 |
| Date: | 28 August 2025 |
| Official Publication: | https://doi.org/10.1038/s41586-025-09240-3 |
| PubMed: | View item in PubMed |
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