Ongoing genome doubling shapes evolvability and immunity in ovarian cancer Journal Article

   

Authors:	McPherson, A.; Vázquez-García, I.; Myers, M. A.; Al-Rawi, D. H.; Zatzman, M.; Weiner, A. C.; Freeman, S.; Mohibullah, N.; Satas, G.; Williams, M. J.; Ceglia, N.; Norkūnaitė, D.; Zhang, A. W.; Li, J.; Lim, J. L. P.; Wu, M.; Choi, S.; Havasov, E.; Grewal, D.; Shi, H.; Kim, M.; Schwarz, R. F.; Kaufmann, T.; Dinh, K. N.; Uhlitz, F.; Tran, J.; Wu, Y.; Patel, R.; Ramakrishnan, S.; Kim, D.; Clarke, J.; Green, H.; Ali, E.; DiBona, M.; Varice, N.; Kundra, R.; Broach, V.; Gardner, G. J.; Roche, K. L.; Sonoda, Y.; Zivanovic, O.; Kim, S. H.; Grisham, R. N.; Liu, Y. L.; Viale, A.; Rusk, N.; Lakhman, Y.; Ellenson, L. H.; Tavaré, S.; Aparicio, S.; Chi, D. S.; Aghajanian, C.; Abu-Rustum, N. R.; Friedman, C. F.; Zamarin, D.; Weigelt, B.; Bakhoum, S. F.; Shah, S. P.
Article Title:	Ongoing genome doubling shapes evolvability and immunity in ovarian cancer
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. © The Author(s) 2025.
Journal Title:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Publication status:	Online ahead of print
Date Published:	2025-07-16
Online Publication Date:	2025-07-16
Language:	English
DOI:	10.1038/s41586-025-09240-3
PROVIDER:	scopus
PUBMED:	40670783
PMCID:	PMC12390843
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105010761554&doi=10.1038%2fs41586-025-09240-3&partnerID=40&md5=40218a97d9767c678e76707622cf79d3
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Sohrab P. Shah -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/227498