Clonal haematopoiesis (CHIP)
As we age, blood stem cells with cancer-like mutations quietly expand in most people. These clones raise leukaemia and heart disease risk, are accelerated by chemotherapy, and confuse blood tests for cancer DNA.
Clonal haematopoiesis of indeterminate potential (CHIP: DNMT3A, TET2, ASXL1, and after chemotherapy PPM1D, TP53, CHEK2 mutations at VAF ≥2%) is present in >10% of people over 70. It confers ~0.5-1%/year progression to myeloid neoplasm, doubles cardiovascular risk via inflammasome-primed macrophages, and predicts therapy-related MDS/AML after PARP inhibitors, platinum, and radioligand therapy. For liquid biopsy, CHIP variants are the main source of false-positive ctDNA calls, so tumour-informed or paired white-cell sequencing is needed. Interventions are preventive (avoid unnecessary genotoxic exposure, monitor) with IL-1β/IL-6 blockade under study.
In one picture
Weeds in the blood's seed bank. Harmless individually, they spread with age and after chemical sprays, some turn into leukaemia, and their DNA litters the blood, so a test for tumour DNA can mistake weeds for cancer.
Diagram
top- Paired white-blood-cell sequencing in liquid biopsy pipelines
- Monitoring after PARP inhibitors and radioligand therapy
- IL-1β/IL-6 blockade trials for CHIP-associated cardiovascular risk
Notes
top- Leading programmes: Ebert (Dana-Farber/Broad) and Jaiswal (Stanford) who defined CHIP; Levine and Bolton (MSK) on therapy-related clonal haematopoiesis.