Clock-like mutational signatures: Linking ageing to endogenous cancer risk

Clock-like mutational signatures, principally the single base substitution signatures SBS1 and SBS5, with smaller contributions from SBS18 and SBS40, accumulate approximately linearly with chronological age across nearly all normal human somatic tissues. Initially viewed as simple molecular odometers of lifetime cell divisions, these signatures are now recognised to reflect a far more complex interplay of replication-associated polymerase errors, spontaneous cytosine deamination, oxidative damage, transcription-coupled processes, R-loop-induced mutagenesis, and tissue-specific repair activities. In this review, we synthesise current progress in defining the biological origins, computational detection, tissue-specific behaviour, and translational potential of these clock-like processes. By integrating insights from large-scale sequencing of normal tissues, single-cell genomics, DNA methylation-based mitotic clocks, and population-level mutational datasets, we explain how a linear mutational input can be reconciled with the exponential rise in cancer incidence predicted by multistage carcinogenesis models. We also evaluate the complementary strengths and limitations of mutational versus epigenetic ageing biomarkers and consider emerging evidence that non-replicative mechanisms may dominate mutagenesis in post-mitotic and metabolically active tissues. Finally, we discuss how a multi-modal "clock architecture" has the potential to transform cancer risk prediction, early detection, and preventive intervention, and we highlight the key unresolved questions and experimental directions needed to translate these fundamental insights into clinical impact.