Epigenetically driven and early immune evasion in colorectal cancer evolution.
Loading...
Embargo End Date
Authors
Lakatos, E
Gunasri, V
Zapata, L
Househam, J
Heide, T
Trahearn, N
Swinyard, O
Cisneros, L
Lynn, C
Mossner, M
Kimberley, C
Spiteri, I
Cresswell, GD
Llibre-Palomar, G
Mitchison, M
Maley, CC
Jansen, M
Rodriguez-Justo, M
Bridgewater, J
Baker, A-M
Sottoriva, A
Graham, TA
Gunasri, V
Zapata, L
Househam, J
Heide, T
Trahearn, N
Swinyard, O
Cisneros, L
Lynn, C
Mossner, M
Kimberley, C
Spiteri, I
Cresswell, GD
Llibre-Palomar, G
Mitchison, M
Maley, CC
Jansen, M
Rodriguez-Justo, M
Bridgewater, J
Baker, A-M
Sottoriva, A
Graham, TA
Document Type
Journal Article
Date
2025-12-01
Date Accepted
2025-08-28
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.
Citation
Nature Genetics, 2025, 57 (12), pp. 3039 - 3049
Source Title
Nature Genetics
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
eISSN
1546-1718
Collections
Research Team
Cancer Genomics
Genomics & evolut dynam
Genomics & evolut dynam