Ongoing genome doubling shapes evolvability and immunity in ovarian cancer
Andrew McPherson, Ignacio Vázquez-Garćıa, Matthew Myers, Duaa H. Al-Rawi, Matthew Zatzman, Adam C. Weiner, Samuel S. Freeman, Neeman Mohibullah, Gryte Satas, Marc Williams, Nicholas Ceglia, Danguolė Norkūnaitė, Allen W. Zhang, Jun Li, Jamie Lim, Michelle Wu, Seongmin Choi, Eliyahu Havasov, Diljot Grewal, Hongyu Shi, Minsoo Kim, Roland F. Schwarz, Tom L. Kaufmann, Khanh N. Dinh, Florian Uhlitz, Julie P. Tran, Yushi Wu, Ruchi Patel, Satish Ramakrishnan, DooA Kim, Justin Clarke, Hunter Green, Emily Ali, Melody Di Bona, 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, Agnès Viale, Nicole Rusk, Yulia Lakhman, Lora H. Ellenson, Simon Tavaré, Samuel Aparício, S. Dennis, Carol Aghajanian, Nadeem R Abu-Rustum, Claire F. Friedman, Dmitriy Zamarin, Britta Weigelt, Samuel F. Bakhoum, Sohrab P. Shah
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. A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.