Publications
Nature geneticsDec 2025 |
57
(
12
),
3039-3049
DOI:
10.1038/s41588-025-02349-1

Epigenetically driven and early immune evasion in colorectal cancer evolution

Lakatos, Eszter; Gunasri, Vinaya; Zapata, Luis; Househam, Jacob; Heide, Timon; Trahearn, Nicholas; Swinyard, Ottilie; Cisneros, Luis; Lynn, Claire; Mossner, Maximilian; Kimberley, Chris; Spiteri, Inmaculada; Cresswell, George D; Llibre-Palomar, Gerard; Mitchison, Miriam; Maley, Carlo C; Jansen, Marnix; Rodriguez-Justo, Manuel; Bridgewater, John; Baker, Ann-Marie; Sottoriva, Andrea; Graham, Trevor A
Product Used
Genes
Abstract
Immune system control is a principal hurdle in cancer evolution. The temporal dynamics of immune evasion remain incompletely characterized, and how immune-mediated selection interrelates with epigenome alteration is unclear. Here we infer the genome- and epigenome-driven evolutionary dynamics of tumor-immune coevolution within primary colorectal cancers (CRCs). We utilize a multiregion multiomic dataset of matched genome, transcriptome and chromatin accessibility profiling from 495 single glands (from 29 CRCs) supplemented with high-resolution spatially resolved neoantigen sequencing data and multiplexed imaging of the tumor microenvironment from 82 microbiopsies within 11 CRCs. Somatic chromatin accessibility alterations contribute to accessibility loss of antigen-presenting genes and silencing of neoantigens. Immune escape and exclusion occur at the outset of CRC formation, and later intratumoral differences in immuno-editing are negligible or exclusive to sites of invasion. Collectively, immune evasion in CRC follows a 'Big Bang' evolutionary pattern, whereby it is acquired close to transformation and defines subsequent cancer-immune evolution.
Product Used
Genes

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