Evolutionary characterization of whole-genome doubling across human cancers

Yangyang Zhang; Haiming Li; Xiaoyu Zhao; Zilong Wang; Yongqi Chen; Sumeng Yang; Shaocong Mo; Jinming Li; Xiaohua Wu; Xu Wang; Shuo Wang; Qinhao Guo

arXiv · 2611.01897

Evolutionary characterization of whole-genome doubling across human cancers

Yangyang Zhang·Haiming Li·Xiaoyu Zhao·Zilong Wang·Yongqi Chen·Sumeng Yang·Shaocong Mo·Jinming Li·Xiaohua Wu·Xu Wang·Shuo Wang·Qinhao Guo

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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.

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Yangyang Zhang, Haiming Li, Xiaoyu Zhao, Zilong Wang, Yongqi Chen, Sumeng Yang, Shaocong Mo, Jinming Li, Xiaohua Wu, Xu Wang, Shuo Wang, Qinhao Guo. 2026-11-01. Evolutionary characterization of whole-genome doubling across human cancers. https://arxiv.org/abs/2611.01897

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