# Ageing tissue and clonal fields: cancer as a disease of old tissue

Source: https://onco.cc/terms/ageing-tissue-field-theory/  
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## TL;DR

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.

## Summary

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.

## Fields

- Kind: Term
- Last checked: 2026-09-17
- Also known as: adaptive oncogenesis; ageing theory of cancer; clonal fields; somatic mosaicism and cancer; cancer as a disease of ageing; field theory of cancer
- Tags: theory

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Clonal_hematopoiesis
- Rozhok and DeGregori, Toward an evolutionary model of cancer: considering the mechanisms that govern the fate of somatic mutations (PNAS 2015): https://doi.org/10.1073/pnas.1501713112
- Laconi, Marongiu and DeGregori, Cancer as a disease of old age: changing mutational and microenvironmental landscapes (British Journal of Cancer 2020): https://doi.org/10.1038/s41416-019-0721-1
- Martincorena et al., Somatic mutant clones colonize the human esophagus with age (Science 2018): https://doi.org/10.1126/science.aau3879
- Jaiswal et al., Age-related clonal hematopoiesis associated with adverse outcomes (NEJM 2014): https://doi.org/10.1056/NEJMoa1408617
- Jaiswal and Ebert, Clonal hematopoiesis in human aging and disease (Science 2019): https://doi.org/10.1126/science.aan4673
- Yoshida et al., Tobacco smoking and somatic mutations in human bronchial epithelium (Nature 2020): https://doi.org/10.1038/s41586-020-1961-1
- Kakiuchi and Ogawa, Clonal expansion in non-cancer tissues (Nature Reviews Cancer 2021): https://doi.org/10.1038/s41568-021-00335-3

## Connected records

- pathways: [Cellular senescence](https://onco.cc/pathways/senescence/), [Clonal haematopoiesis (CHIP)](https://onco.cc/pathways/clonal-haematopoiesis/), [Field cancerisation](https://onco.cc/pathways/field-cancerisation/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/), [Theories of cancer: how the ideas connect](https://onco.cc/pathways/theories-of-cancer/)
- terms: [Clonal evolution and the ecological view of cancer](https://onco.cc/terms/clonal-evolution-theory/), [Driver and passenger mutations: the refined somatic mutation theory](https://onco.cc/terms/driver-passenger-model/), [Epigenetic progenitor theory: cancer without a first mutation](https://onco.cc/terms/epigenetic-progenitor-theory/), [Hallmark (2022): senescent cells](https://onco.cc/terms/senescent-cells/), [Microenvironment and inflammation: tumours as wounds that do not heal](https://onco.cc/terms/microenvironment-inflammation-theory/), [Somatic mutation theory of cancer](https://onco.cc/terms/somatic-mutation-theory/), [Variant allele frequency (VAF)](https://onco.cc/terms/vaf/)
- technologies: [Cancer interception vaccines](https://onco.cc/technologies/interception-vaccination/), [Chemoprevention & risk-reducing surgery](https://onco.cc/technologies/chemoprevention/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/)
- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/), [Oesophageal cancer](https://onco.cc/cancers/esophageal/)
- targets: [TP53](https://onco.cc/targets/tp53/)
- people: [Benjamin L. Ebert](https://onco.cc/people/benjamin-ebert/), [Charles Swanton](https://onco.cc/people/charles-swanton/), [Michael Stratton](https://onco.cc/people/michael-stratton/)
- key papers: [Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70](https://onco.cc/key-papers/paper-jaiswal-chip-nejm-2014/), [Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones](https://onco.cc/key-papers/paper-martincorena-somatic-mutations-normal-skin-science-2015/)

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