Fluctuating DNA methylation tracks cancer evolution at clinical scale

Calum Gabbutt (), Martí Duran-Ferrer, Heather E. Grant, Diego Mallo, Ferran Nadeu, Jacob Househam, Neus Villamor, Madlen Müller, Simon Heath, Emanuele Raineri, Olga Krali, Jessica Nordlund, Thorsten Zenz, Ivo G. Gut, Elias Campo, Armando Lopez-Guillermo, Jude Fitzgibbon, Chris P. Barnes, Darryl Shibata, José I. Martin-Subero () and Trevor A. Graham ()
Additional contact information
Calum Gabbutt: Institute of Cancer Research
Martí Duran-Ferrer: Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS)
Heather E. Grant: Institute of Cancer Research
Diego Mallo: Arizona State University
Ferran Nadeu: Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS)
Jacob Househam: Institute of Cancer Research
Neus Villamor: Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS)
Madlen Müller: Centro Nacional de Analisis Genomico (CNAG)
Simon Heath: Centro Nacional de Analisis Genomico (CNAG)
Emanuele Raineri: Centro Nacional de Analisis Genomico (CNAG)
Olga Krali: Uppsala University
Jessica Nordlund: Uppsala University
Thorsten Zenz: University Hospital and University of Zürich
Ivo G. Gut: Centro Nacional de Analisis Genomico (CNAG)
Elias Campo: Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS)
Armando Lopez-Guillermo: Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS)
Jude Fitzgibbon: Queen Mary University of London
Chris P. Barnes: University College London
Darryl Shibata: University of Southern California
José I. Martin-Subero: Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS)
Trevor A. Graham: Institute of Cancer Research

Nature, 2025, vol. 645, issue 8081, 764-773

Abstract: Abstract Cancer development and response to treatment are evolutionary processes1,2, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging3. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time4, 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.

Date: 2025
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DOI: 10.1038/s41586-025-09374-4

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