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Peer-reviewedCC BYScience Advances

Evidence of active whole-genome doubling (WGD) subclones in non-WGD tumors

  • Funan He1,2
  • Mehwish Noureen1,2
  • Eloise Dray1,3,4
  • Myron S. Ignatius1,4,5
  • Xiaojing Wang1,2,4,6
  • Siyuan Zheng1,2,4
6 affiliations
  1. 1Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA.
  2. 2Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA.
  3. 3Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, TX, USA.
  4. 4Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA.
  5. 5Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, USA.
  6. 6Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX, USA.
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Abstract

Whole-genome doubling (WGD) occurs frequently in human cancer and influences tumor evolution, metastasis, and treatment response. Here, we integrate bulk, single-cell, and spatial data to dissect the subclonal dynamics of WGD. Single-cell data analysis shows that WGD cells are prevalent even in tumors that are classified as non-WGD (nWGD). WGD subclones actively acquire somatic copy number alterations as they expand, suggesting ongoing evolution. We developed and rigorously validated a gene expression-based method, WAGES, to map WGD cell clonal fraction in bulk tumors. Applying WAGES to nWGD tumors, we reveal genomic correlates including TP53 mutations and chromosomal instability that are consistent with the presence of WGD subclones. Clinically, WAGES scores are strongly correlated with tumor metastatic potential, response to treatments including chemotherapy and immunotherapy, and patient prognosis. These findings reveal widespread WGD subclones in nWGD tumors and demonstrate their substantial impact on cancer evolution and therapeutic outcomes.

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Cite

BibTeXRIS
BibTeX
@article{he2026evidence,
  title = {{Evidence of active whole-genome doubling (WGD) subclones in non-WGD tumors}},
  author = {Funan He and Mehwish Noureen and Eloise Dray and Myron S. Ignatius and Xiaojing Wang and Siyuan Zheng},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aee7939},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aee7939},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Evidence of active whole-genome doubling (WGD) subclones in non-WGD tumors
AU  - Funan He
AU  - Mehwish Noureen
AU  - Eloise Dray
AU  - Myron S. Ignatius
AU  - Xiaojing Wang
AU  - Siyuan Zheng
PY  - 2026
DA  - 2026/10/30
JO  - Science Advances
DO  - 10.1126/sciadv.aee7939
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aee7939
AB  - Whole-genome doubling (WGD) occurs frequently in human cancer and influences tumor evolution, metastasis, and treatment response. Here, we integrate bulk, single-cell, and spatial data to dissect the subclonal dynamics of WGD. Single-cell data analysis shows that WGD cells are prevalent even in tumors that are classified as non-WGD (nWGD). WGD subclones actively acquire somatic copy number alterations as they expand, suggesting ongoing evolution. We developed and rigorously validated a gene expression-based method, WAGES, to map WGD cell clonal fraction in bulk tumors. Applying WAGES to nWGD tumors, we reveal genomic correlates including TP53 mutations and chromosomal instability that are consistent with the presence of WGD subclones. Clinically, WAGES scores are strongly correlated with tumor metastatic potential, response to treatments including chemotherapy and immunotherapy, and patient prognosis. These findings reveal widespread WGD subclones in nWGD tumors and demonstrate their substantial impact on cancer evolution and therapeutic outcomes.
SN  - 2375-2548
ER  -