Fluctuating DNA methylation tracks cancer evolution at clinical scale
Cancer development and response to treatment are evolutionary processes<sup>1,2</sup>, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging<sup>3</sup>. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time<sup>4</sup>, that quantitatively infers evolutionary dynamics using only a bulk tumour methylation profile as input. We apply EVOFLUx to 1,976 well-characterized lymphoid cancer samples spanning a broad spectrum of diseases and show that initial tumour growth rate, malignancy age and epimutation rates vary by orders of magnitude across disease types. We measure that subclonal selection occurs only infrequently within bulk samples and detect occasional examples of multiple independent primary tumours. Clinically, we observe faster initial tumour growth in more aggressive disease subtypes, and that evolutionary histories are strong independent prognostic factors in two series of chronic lymphocytic leukaemia. Using EVOFLUx for phylogenetic analyses of aggressive Richter-transformed chronic lymphocytic leukaemia samples detected that the seed of the transformed clone existed decades before presentation. Orthogonal verification of EVOFLUx inferences is provided using additional genetic data, including long-read nanopore sequencing, and clinical variables. Collectively, we show how widely available, low-cost bulk DNA methylation data precisely measure cancer evolutionary dynamics, and provides new insights into cancer biology and clinical behaviour.
Authors
- Heather E. Grant (ORCID: https://orcid.org/0000-0001-9500-1644)
- Thorsten Zenz (ORCID: https://orcid.org/0000-0001-7890-9845)
- Diego Mallo (ORCID: https://orcid.org/0000-0002-9046-8859)
- Armando López‐Guillermo
- Martí Duran‐Ferrer (ORCID: https://orcid.org/0000-0003-1666-5819)
- José I. Martı́n-Subero (ORCID: https://orcid.org/0000-0001-8809-5195)
- Neus Villamor (ORCID: https://orcid.org/0000-0001-6538-4111)
- Darryl Shibata (ORCID: https://orcid.org/0000-0002-4567-1639)
- Elı́as Campo (ORCID: https://orcid.org/0000-0001-9850-9793)
- C. Barnes (ORCID: https://orcid.org/0000-0002-9459-1395)
- Jacob Househam (ORCID: https://orcid.org/0000-0003-3199-336X)
- Trevor A. Graham (ORCID: https://orcid.org/0000-0001-9582-1597)
- Olga Krali (ORCID: https://orcid.org/0000-0002-6436-9531)
- Madlen Müller (ORCID: https://orcid.org/0000-0002-1381-7517)
- Ferran Nadeu (ORCID: https://orcid.org/0000-0003-2910-9440)
- Emanuele Raineri (ORCID: https://orcid.org/0000-0003-1932-311X)
- Calum Gabbutt (ORCID: https://orcid.org/0000-0003-1946-4780)
- Jessica Nordlund (ORCID: https://orcid.org/0000-0001-8699-9959)
- Jude Fitzgibbon
- Simon Heath (ORCID: https://orcid.org/0000-0002-9550-0897)
Institutions
- University of Southern California (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Uppsala University (SE)
- Institute of Cancer Research (GB)
- Queen Mary University of London (GB)
- Science for Life Laboratory (SE)
- Cancer Research UK (GB)
- University Hospital of Zurich (CH)
- NIHR Imperial Biomedical Research Centre (GB)
- Hospital Clínic de Barcelona (ES)
- Center for Pediatric Endocrinology Zurich (CH)
- Centro Nacional de Análisis Genómico (ES)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (ES)
- University College London (GB)
- Imperial College London (GB)
- Arizona State University (US)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature
- Published
- 2025-09-10
- DOI
- https://doi.org/10.1038/s41586-025-09374-4
- Citations
- 10
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 8.06