Abstract
Therapeutic advances have improved cancer outcomes, but early-stage detection remains the single most important determinant of favorable prognoses across many cancer types. Cancer genomics has yielded detailed maps of somatic mutation and methylation patterns characteristic of different cancers, enabling the development of assays to detect mutation-bearing tumor-derived DNA in tissue biopsies, blood and other body fluids at the earliest stages of disease. In parallel, it has also become clear that small clones bearing cancer-associated mutations arise commonly in histologically normal tissues, a phenomenon that becomes universal in proliferative tissues with age but leads to cancer in only a small minority of individuals. This review article outlines established strategies for early cancer detection and highlights emerging insights into the genetics of precancerous mutant clones that have led to the recent development of prognostic frameworks for identifying high-risk individuals, making it increasingly possible to intercept evolving cancer at a premalignant or early malignant stage, when interventions are most effective.
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Acknowledgements
G.S.V. is part-funded by the Cancer Research UK Cambridge Centre (Cancer Research UK Major Centre Awards C9685/A25117 and CTRQQR-2021\100012) and work in his lab is supported by a Blood Cancer United/Blood Cancer UK Specialized Centre of Research Grant (7035-24), an Early Detection Project Grant from Cancer Research UK (EDDCPJT\100010), the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014 and NIHR203312), the European Research Council, Kay Kendall Leukaemia Fund, Blood Cancer UK and the Wellcome Trust. M.G. was supported by Blood Cancer United/Blood Cancer UK Specialized Centre of Research Grant (7035-24). W.Z.Z. is supported by a Cancer Research UK studentship award (G122225). A.M.F. is supported by a Wellcome Trust Career Development Award (319560/Z/24/Z) and an Academy of Medical Sciences Springboard Award (SBF0010\1072). Work in the R.C.F. laboratory is supported by the Medical Research Council (MR/W014122/1) with infrastructure support from the CRUK Major Centre.
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M.G. and W.Z.Z. contributed equally to the writing of this review. G.S.V. and A.M.F. cowrote and supervised the review with the input from R.C.F.
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G.S.V. is a consultant for STRM.BIO and Athernal Bio, and receives a research grant from AstraZeneca. R.C.F. is named on patents relating to Cytosponge and associated assays that have been licensed by the Medical Research Council to Covidien GI solutions (now Medtronic) and is a cofounder and shareholder (<2%) of Cyted. A.M.F. is a co-inventor on a patent application to determine methods and systems for tumor monitoring (PCT/EP2022/077987). The other authors declare no competing interests.
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Gu, M., Zhang, W.Z., Fitzgerald, R.C. et al. Harnessing genomics for early cancer detection, risk stratification and prevention. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02505-1
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DOI: https://doi.org/10.1038/s41588-026-02505-1
