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Ongoing genome doubling shapes evolvability and immunity in ovarian cancer

Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1-6. 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,...

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Main Authors: McPherson, Andrew (Author) , Vázquez-García, Ignacio (Author) , Myers, Matthew A. (Author) , Al-Rawi, Duaa H. (Author) , Zatzman, Matthew (Author) , Weiner, Adam C. (Author) , Freeman, Samuel (Author) , Mohibullah, Neeman (Author) , Satas, Gryte (Author) , Williams, Marc J. (Author) , Ceglia, Nicholas (Author) , Norkūnaitė, Danguolė (Author) , Zhang, Allen W. (Author) , Li, Jun (Author) , Lim, Jamie L. P. (Author) , Wu, Michelle (Author) , Choi, Seongmin (Author) , Havasov, Eliyahu (Author) , Grewal, Diljot (Author) , Shi, Hongyu (Author) , Kim, Minsoo (Author) , Schwarz, Roland F. (Author) , Kaufmann, Tom (Author) , Dinh, Khanh Ngoc (Author) , Uhlitz, Florian (Author) , Tran, Julie (Author) , Wu, Yushi (Author) , Patel, Ruchi (Author) , Ramakrishnan, Satish (Author) , Kim, DooA (Author) , Clarke, Justin (Author) , Green, Hunter (Author) , Ali, Emily (Author) , DiBona, Melody (Author) , Varice, Nancy (Author) , Kundra, Ritika (Author) , Broach, Vance (Author) , Gardner, Ginger J. (Author) , Roche, Kara Long (Author) , Sonoda, Yukio (Author) , Zivanovic, Oliver (Author) , Kim, Sarah H. (Author) , Grisham, Rachel N. (Author) , Liu, Ying L. (Author) , Viale, Agnes (Author) , Rusk, Nicole (Author) , Lakhman, Yulia (Author) , Ellenson, Lora H. (Author) , Tavaré, Simon (Author) , Aparicio, Samuel (Author) , Chi, Dennis S. (Author) , Aghajanian, Carol (Author) , Abu-Rustum, Nadeem R. (Author) , Friedman, Claire F. (Author) , Zamarin, Dmitriy (Author) , Weigelt, Britta (Author) , Bakhoum, Samuel F. (Author) , Shah, Sohrab P. (Author)
Format: Article (Journal)
Language:English
Published: 16 July 2025
In: Nature
Year: 2025, Volume: 644, Issue: 8078, Pages: 1078-1087, [1-29]
ISSN:1476-4687
DOI:10.1038/s41586-025-09240-3
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41586-025-09240-3
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41586-025-09240-3
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Author Notes:Andrew McPherson, Ignacio Vázquez-García, Matthew A. Myers, Duaa H. Al-Rawi, Matthew Zatzman, Adam C. Weiner, Samuel Freeman, Neeman Mohibullah, Gryte Satas, Marc J. Williams, Nicholas Ceglia, Danguolė Norkūnaitė, Allen W. Zhang, Jun Li, Jamie L.P. Lim, Michelle Wu, Seongmin Choi, Eliyahu Havasov, Diljot Grewal, Hongyu Shi, Minsoo Kim, Roland F. Schwarz, Tom Kaufmann, Khanh Ngoc Dinh, Florian Uhlitz, Julie Tran, Yushi Wu, Ruchi Patel, Satish Ramakrishnan, DooA Kim, Justin Clarke, Hunter Green, Emily Ali, Melody DiBona, Nancy Varice, Ritika Kundra, Vance Broach, Ginger J. Gardner, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Sarah H. Kim, Rachel N. Grisham, Ying L. Liu, Agnes Viale, Nicole Rusk, Yulia Lakhman, Lora H. Ellenson, Simon Tavaré, Samuel Aparicio, Dennis S. Chi, Carol Aghajanian, Nadeem R. Abu-Rustum, Claire F. Friedman, Dmitriy Zamarin, Britta Weigelt, Samuel F. Bakhoum & Sohrab P. Shah
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Summary:Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1-6. 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.
Item Description:Gesehen am 01.12.2025
Physical Description:Online Resource
ISSN:1476-4687
DOI:10.1038/s41586-025-09240-3

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