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.
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.
Tumour genomes are grossly altered at the chromosome scale in most cancer types. Copy number alterations (CNAs), entire chromosome gains and losses, and whole genome duplication (WGD) are generated by Chromosomal instability (CIN) and shaped by evolutionary selection. Cancer genomics studies have widely demonstrated th...
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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 classifi...
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