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

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.