Evolutionary characterization of whole-genome doubling across human cancers

Abstract

Whole-genome doubling (WGD) is common across human cancers and is associated with tumour progression and adverse clinical outcomes. However, how genome-doubled tumours evolve across diverse cancer types remains poorly understood. Here we characterize WGD-associated tumour evolution by integrating genomic analyses of 41,332 tumours from 12 cancer types with evolutionary timing and multi-omic data. Several canonical driver mutations generally preceded WGD when both occurred, as did the onset of homologous recombination deficiency-associated mutagenesis. Notably, post-WGD chromosome-arm losses showed substantially weaker cancer-type dependence than pre-WGD losses, with 61-75% less variance explained by cancer type. Beyond chromosomal evolution, WGD+ tumours showed reduced interferon-response and HLA antigen-presentation programmes linked to epigenetic remodelling, without disproportionate enrichment of genetic immune-escape alterations. Our findings highlight WGD as a recurrent evolutionary transition associated with altered chromosomal evolution and epigenetically linked immune adaptation across cancers.