Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70
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.
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.
- 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
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.
- 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
Pages like this
not linked directly; found by shared links- IdeaPush residual disease detection a hundredfold deeper with whole-genome methods
Shares Variant allele frequency (VAF), Whole-exome & whole-genome sequencing, Circulating tumour DNA (ctDNA), Most lethal cancers are found late.
- Key paperGerlinger: a single biopsy misses most of the mutations in a kidney tumour
Shares Variant allele frequency (VAF), Clonal evolution & minimal residual disease, Whole-exome & whole-genome sequencing, Biomarkers are not validated or standardised.
- IdeaCertified reference samples to benchmark every tumour-DNA blood test
Shares Variant allele frequency (VAF), Circulating tumour DNA (ctDNA), Biomarkers are not validated or standardised, Liquid biopsy (ctDNA).
- IdeaAn annual blinded shoot-out for liquid biopsy tests
Shares Variant allele frequency (VAF), Circulating tumour DNA (ctDNA), Biomarkers are not validated or standardised, Liquid biopsy (ctDNA).
- InstitutionHoward Hughes Medical Institute
Shares Benjamin L. Ebert, Broad Institute of MIT and Harvard, Dana-Farber Brigham Cancer Center.
- Key paperGALAXY: tumour DNA in blood four weeks after bowel cancer surgery predicts relapse tenfold
Shares Variant allele frequency (VAF), Circulating tumour DNA (ctDNA), Biomarkers are not validated or standardised, Liquid biopsy (ctDNA).
- IdeaA clone report from blood at every treatment cycle
Shares Variant allele frequency (VAF), Circulating tumour DNA (ctDNA), Liquid biopsy (ctDNA).
- InstitutionCancer Research UK Cambridge Centre / CRUK Cambridge Institute
Shares Whole-exome & whole-genome sequencing, Circulating tumour DNA (ctDNA), Most lethal cancers are found late, Liquid biopsy (ctDNA).