# Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70

Source: https://onco.cc/key-papers/paper-jaiswal-chip-nejm-2014/  
OnCo record `paper-jaiswal-chip-nejm-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Blood DNA from 17,182 people showed that clones carrying leukaemia-associated mutations (mostly DNMT3A, TET2, ASXL1) are present in about 10% of people over 70, raising the risk of blood cancer 11-fold and, unexpectedly, of heart attack and stroke.

## Summary

Exome sequences generated for diabetes genetics studies were mined for somatic mutations in genes recurrently mutated in blood cancers. Clonal haematopoiesis of indeterminate potential (CHIP) was rare under 40 but present in 9.5% of people aged 70-79 and 18.4% over 90.

Carriers had an 11-fold higher risk of subsequent haematological cancer, though the absolute rate was modest (about 0.5-1% per year). Strikingly, CHIP was associated with higher all-cause mortality (HR 1.4), driven by cardiovascular disease: coronary heart disease HR 2.0 and ischaemic stroke HR 2.6. A companion paper (Genovese, NEJM 2014) reported the same phenomenon in a Swedish cohort.

CHIP is now recognised as a common age-related premalignant state, a driver of cardiovascular inflammation, a source of false positives in ctDNA tests, and a target for prevention.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2014
- DOI: 10.1056/NEJMoa1408617
- Authors: Jaiswal S, Fontanillas P, Flannick J, et al.
- Findings: CHIP prevalence 9.5% at ages 70-79 and 18.4% over 90, versus under 1% below 40; Haematological cancer risk HR 11.1 (95% CI 3.9-32.6); absolute risk about 0.5-1% per year; All-cause mortality HR 1.4; coronary heart disease HR 2.0; ischaemic stroke HR 2.6; Most common mutated genes: DNMT3A, TET2, ASXL1
- What it means: 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.
- Caveats: Cross-sectional discovery with limited follow-up; the leukaemia progression rate was estimated from a small number of events; Exome sequencing at modest depth detects only clones above about 2% variant allele fraction; Cohorts were ascertained for metabolic disease, which may inflate cardiovascular associations; No intervention has yet been shown to reduce CHIP-related risk

## Sources

- DOI: https://doi.org/10.1056/NEJMoa1408617
- Genovese 2014 companion paper: https://doi.org/10.1056/NEJMoa1409405

## Connected records

- key papers: [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/)
- ideas: [Which patients' blood clones will become leukaemia after treatment?](https://onco.cc/ideas/idea-chip-risk-modifiers/)
- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/)
- fronts: [Early Detection & Screening](https://onco.cc/fronts/early-detection/), [Prevention & Risk](https://onco.cc/fronts/prevention/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/), [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Clonal haematopoiesis (CHIP)](https://onco.cc/pathways/clonal-haematopoiesis/)
- terms: [Ageing tissue and clonal fields: cancer as a disease of old tissue](https://onco.cc/terms/ageing-tissue-field-theory/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Variant allele frequency (VAF)](https://onco.cc/terms/vaf/)
- people: [Benjamin L. Ebert](https://onco.cc/people/benjamin-ebert/), [C. Ola Landgren](https://onco.cc/people/ola-landgren/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Older and multimorbid patients are excluded and undertreated](https://onco.cc/bottlenecks/b-aging-comorbidity/), [The hardest cancers are found late](https://onco.cc/bottlenecks/b-early-detection/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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