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Ongoing Genome Doubling in Ovarian Cancer

Generated from Ongoing genome doubling shapes evolvability and immunity in ovarian cancer

Ongoing genome doubling shapes evolvability and immunity in ovarian cancer (McPherson et al., 2025), published in Nature, asks what whole-genome doubling (WGD), the duplication of a cell's entire genome, does to high-grade serous ovarian cancer: how it changes the way tumors evolve, and how they evade the immune system. The authors followed it at single-cell resolution in tumors from the MSK SPECTRUM cohort.

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Key Findings

  • Genome doubling is ongoing. The authors found near-ubiquitous evidence that WGD is not a single early event but keeps happening as tumors grow: early doubling followed by diversification, repeated doubling in parallel lineages, and late doubling in small clones and single cells.
  • Doubled tumors missegregate more. WGD went with more cell-to-cell diversity and higher rates of chromosome missegregation and the micronuclei that result from it.
  • Doubled tumors silence an immune alarm. In mostly diploid (WGD-low) tumors, ongoing chromosomal instability switched on inflammatory signaling through cGAS–STING. Mostly doubled (WGD-high) tumors, despite more missegregation, repressed STING1 and showed immunosuppressive states.

The Data

  • Single-cell whole-genome sequencing: 30,260 tumor genomes from 70 samples from 41 patients, untreated at diagnosis.
  • Immunofluorescence: site-matched staining for micronuclei and DNA sensing (cGAS, STING), the measurements behind the charts below.
  • Single-cell RNA sequencing: matched to the same patients.

Paper: McPherson A, Vázquez-García I, Myers MA, et al. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer. Nature 644, 1078–1087 (2025). doi:10.1038/s41586-025-09240-3

Genome-Doubled Tumors Make More Micronuclei but Silence STING

When chromosomes are missegregated, fragments end up in small micronuclei outside the main nucleus. Normally the cGAS–STING pathway senses that stray DNA and raises an immune alarm. Whole-genome doubled (WGD) tumors make more micronuclei, yet express less STING: the alarm that diploid tumors keep is switched off, which helps doubled tumors hide from the immune system.

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Rate of micronuclei by WGD class: higher in genome-doubled tumors.

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Each square is one microscope field on an omentum slide, colored by micronuclei per nucleus. Left, a genome-doubled tumor (OV-051): 0.032 micronuclei per nucleus over the slide. Right, a mostly diploid tumor (OV-007): 0.018. Each is the high-quality slide closest to its group's median.

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STING by WGD class: lower in genome-doubled tumors.

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Each point is an immunofluorescence slide, colored by WGD class and sized by cGAS: doubled tumors tend to sit further right (more micronuclei) and lower (less STING).

CD8 T-Cell Dysfunction Follows the Mutational Signature

Among tumors whose mutations point to faulty homologous recombination repair, how dysfunctional the tumor's CD8 T cells are depends on the specific mutational signature rather than on genome doubling.

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One point per patient, grouped by mutational signature.
Discovery Lab

About These Charts

These charts were built in the Discovery Lab TRE from the study's immunofluorescence measurements (a6b4ad12), with WGD class and mutational signature from the authors' analysis (tables fa1ba693 and 1a147d21).