Ongoing genome doubling shapes evolvability and immunity in ovarian cancer
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 and
Sohrab P. Shah ()
Additional contact information
Andrew McPherson: Memorial Sloan Kettering Cancer Center
Ignacio Vázquez-García: Memorial Sloan Kettering Cancer Center
Matthew A. Myers: Memorial Sloan Kettering Cancer Center
Duaa H. Al-Rawi: Memorial Sloan Kettering Cancer Center
Matthew Zatzman: Memorial Sloan Kettering Cancer Center
Adam C. Weiner: Memorial Sloan Kettering Cancer Center
Samuel Freeman: Memorial Sloan Kettering Cancer Center
Neeman Mohibullah: Memorial Sloan Kettering Cancer Center
Gryte Satas: Memorial Sloan Kettering Cancer Center
Marc J. Williams: Memorial Sloan Kettering Cancer Center
Nicholas Ceglia: Memorial Sloan Kettering Cancer Center
Danguolė Norkūnaitė: Memorial Sloan Kettering Cancer Center
Allen W. Zhang: University of British Columbia
Jun Li: Memorial Sloan Kettering Cancer Center
Jamie L. P. Lim: Memorial Sloan Kettering Cancer Center
Michelle Wu: Memorial Sloan Kettering Cancer Center
Seongmin Choi: Memorial Sloan Kettering Cancer Center
Eliyahu Havasov: Memorial Sloan Kettering Cancer Center
Diljot Grewal: Memorial Sloan Kettering Cancer Center
Hongyu Shi: Memorial Sloan Kettering Cancer Center
Minsoo Kim: Memorial Sloan Kettering Cancer Center
Roland F. Schwarz: University of Cologne
Tom Kaufmann: BIFOLD - Berlin Institute for the Foundations of Learning and Data
Khanh Ngoc Dinh: Columbia University
Florian Uhlitz: Memorial Sloan Kettering Cancer Center
Julie Tran: Memorial Sloan Kettering Cancer Center
Yushi Wu: Memorial Sloan Kettering Cancer Center
Ruchi Patel: Memorial Sloan Kettering Cancer Center
Satish Ramakrishnan: Memorial Sloan Kettering Cancer Center
DooA Kim: Memorial Sloan Kettering Cancer Center
Justin Clarke: Memorial Sloan Kettering Cancer Center
Hunter Green: Memorial Sloan Kettering Cancer Center
Emily Ali: Memorial Sloan Kettering Cancer Center
Melody DiBona: Memorial Sloan Kettering Cancer Center
Nancy Varice: Memorial Sloan Kettering Cancer Center
Ritika Kundra: Memorial Sloan Kettering Cancer Center
Vance Broach: Memorial Sloan Kettering Cancer Center
Ginger J. Gardner: Memorial Sloan Kettering Cancer Center
Kara Long Roche: Memorial Sloan Kettering Cancer Center
Yukio Sonoda: Memorial Sloan Kettering Cancer Center
Oliver Zivanovic: Memorial Sloan Kettering Cancer Center
Sarah H. Kim: Memorial Sloan Kettering Cancer Center
Rachel N. Grisham: Memorial Sloan Kettering Cancer Center
Ying L. Liu: Memorial Sloan Kettering Cancer Center
Agnes Viale: Memorial Sloan Kettering Cancer Center
Nicole Rusk: Memorial Sloan Kettering Cancer Center
Yulia Lakhman: Weill Cornell Medical Center
Lora H. Ellenson: Memorial Sloan Kettering Cancer Center
Simon Tavaré: Columbia University
Samuel Aparicio: BC Cancer
Dennis S. Chi: Memorial Sloan Kettering Cancer Center
Carol Aghajanian: Memorial Sloan Kettering Cancer Center
Nadeem R. Abu-Rustum: Memorial Sloan Kettering Cancer Center
Claire F. Friedman: Memorial Sloan Kettering Cancer Center
Dmitriy Zamarin: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Sohrab P. Shah: Memorial Sloan Kettering Cancer Center
Nature, 2025, vol. 644, issue 8078, 1078-1087
Abstract:
Abstract 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.
Date: 2025
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DOI: 10.1038/s41586-025-09240-3
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