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Sequencing of healthy skin, gullet and blood shows that by middle age they are patchworks of mutant clones, many carrying classic cancer mutations, yet cancer stays rare until old age. The ageing tissue view says the mutations are there early and it is the tissue that changes: ageing, damage and inflammation alter which clones win. Clonal haematopoiesis in the blood is the best-measured example.
The claim. Mutations accumulate in normal tissue throughout life, roughly in proportion to age, and driver mutations are under positive selection in healthy tissue decades before any cancer. Cancer incidence nonetheless rises as a high power of age. DeGregori's adaptive oncogenesis model resolves this by arguing that a young, healthy tissue is a landscape in which normal stem cells are already near optimal fitness, so most oncogenic mutations offer no advantage; ageing, chronic inflammation, smoking and other damage degrade the landscape, and the same mutations then give their clones an edge. Field cancerisation (Slaughter 1953) is the histological version: the cancer is the one clone that got furthest in a field of pre-malignant tissue.
Who and when. Armitage and Doll's 1954 age-incidence curves. Slaughter's field cancerisation in oral cancer, 1953. Rozhok and DeGregori set out adaptive oncogenesis in 2015 and Laconi, Marongiu and DeGregori reviewed cancer as a disease of old age in 2020. Jaiswal, Ebert and colleagues and Genovese and colleagues described clonal haematopoiesis of indeterminate potential in 2014; Martincorena and Stratton sequenced normal skin in 2015 and normal oesophagus in 2018; Yoshida and colleagues showed in 2020 that stopping smoking allows undamaged bronchial clones to re-expand; Kakiuchi and Ogawa reviewed clonal expansion in non-cancer tissues in 2021.
Evidence for. Normal oesophagus in middle age is largely colonised by clones carrying NOTCH1 and TP53 mutations, and NOTCH1 mutations are more frequent in normal oesophagus than in oesophageal cancer, so a driver in normal tissue is not the same as a driver of cancer. Clonal haematopoiesis is present in a large minority of people over seventy, carries a measurable annual risk of progression to myeloid neoplasm, and is selected by chemotherapy, which explains therapy-related leukaemia. Mutation burden in normal tissue rises linearly with age while cancer incidence rises steeply, which fits a change in selection rather than in mutation supply. Transplantation experiments show old bone marrow microenvironments favour mutant clones.
Evidence against and limits. Some cancers peak in childhood or young adulthood, where the model must appeal to developmental tissue states. Immune ageing offers a competing explanation for the late rise in incidence. The model is difficult to separate experimentally from simple mutation accumulation, and it has not yet produced an intervention shown to lower cancer incidence.
Predictions that held or failed. Held: driver mutations are common in normal tissue; clonal haematopoiesis predicts leukaemia and cardiovascular disease; chemotherapy and radiotherapy select pre-existing mutant blood clones; smoking cessation shifts clonal composition. Unfulfilled: prevention by rejuvenating tissue or clearing senescent cells is untested in humans.
Therapies that came from it. None yet. Its practical products are clonal haematopoiesis clinics, awareness that clonal haematopoiesis causes false positive liquid biopsy results, and the prevention and interception agenda: treating fields rather than tumours, chemoprevention and anti-inflammatory strategies. It extends clonal evolution backwards into normal life and joins it to the microenvironment view.
Status: partly confirmed. The colonisation of normal tissue by mutant clones is established; that changing selection in ageing tissue, rather than mutation count, drives the age-incidence curve is well supported but still being tested.
In plain words · TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
Showing the target this term concerns: TP53.
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Carrying a cancer mutation is normal; most mutant clones never become cancer. This means blood or tissue tests that look for driver mutations alone will produce false positives, and that the question of what tips a mutant clone into cancer (tissue environment, further hits, immune surveillance) is as important as the mutation itself.
Many older people carry blood clones one or two steps from leukaemia, and those clones also drive heart disease through inflammation. CHIP is why blood-based cancer tests must filter out mutations from blood cells, and it opens a route to preventing both leukaemia and cardiovascular events in carriers.
Shares Michael Stratton, Charles Swanton, Clonal evolution and the ecological view of cancer, Theories of cancer: how the ideas connect and the tag theory.
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Shares Epigenetic progenitor theory: cancer without a first mutation, Theories of cancer: how the ideas connect, Somatic mutation theory of cancer and the tag theory.
Shares Epigenetic progenitor theory: cancer without a first mutation, Theories of cancer: how the ideas connect, Somatic mutation theory of cancer, Acute myeloid leukaemia and the tag theory.
Shares Microenvironment and inflammation: tumours as wounds that do not heal, Theories of cancer: how the ideas connect, Somatic mutation theory of cancer and the tag theory.
Shares Epigenetic progenitor theory: cancer without a first mutation, Clonal evolution and the ecological view of cancer, Theories of cancer: how the ideas connect, Acute myeloid leukaemia and the tag theory.
Shares Clonal evolution and the ecological view of cancer, Theories of cancer: how the ideas connect, Somatic mutation theory of cancer and the tag theory.
Shares Clonal evolution and the ecological view of cancer, Microenvironment and inflammation: tumours as wounds that do not heal, Theories of cancer: how the ideas connect and the tag theory.