{"entity":{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Clonal_hematopoiesis","links":[{"label":"Jaiswal et al., Age-related clonal hematopoiesis associated with adverse outcomes (NEJM 2014)","url":"https://doi.org/10.1056/NEJMoa1408617"},{"label":"Bolton et al., Cancer therapy shapes the fitness landscape of clonal hematopoiesis (Nature Genetics 2020)","url":"https://doi.org/10.1038/s41588-020-00710-0"}],"tags":["mechanism"],"related":["ageing-tissue-field-theory"],"cancers":["aml","prostate","prostate-mcrpc"],"sections":[],"technologies":["liquid-biopsy","mrd-testing","parp-inhibitor"],"targets":["tp53","parp","tet2"],"drugs":[],"companies":[],"institutions":["dana-farber","broad-institute","mskcc"],"pathways":["clonal-evolution","inflammation-nfkb","epigenetic-reprogramming"],"terms":["vaf","ctdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","paper-bolton-nat-genet"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Ebert (Dana-Farber/Broad) and Jaiswal (Stanford) who defined CHIP; Levine and Bolton (MSK) on therapy-related clonal haematopoiesis.","Prostate cancer: this is where clonal haematopoiesis does concrete harm. In 69 men with advanced prostate cancer, clonal haematopoiesis variants at 2% or more were present in plasma from 13, 19%, and 7, 10%, had one in a gene used to decide PARP inhibitor candidacy, most often ATM, accounting for almost half of all somatic DNA repair variants detected. A paired whole-blood control distinguishes them (Jensen 2021)."],"analogy":"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.","nodes":[{"id":"hsc","label":"Ageing HSCs","x":15,"y":50},{"id":"mut","label":"DNMT3A, TET2, ASXL1, PPM1D, TP53","x":40,"y":50,"targetId":"tp53"},{"id":"chip","label":"CHIP clone (VAF ≥2%)","x":65,"y":50},{"id":"mds","label":"Therapy-related MDS/AML","x":90,"y":25},{"id":"cvd","label":"Inflammation → cardiovascular disease","x":90,"y":60},{"id":"fp","label":"False-positive ctDNA","x":90,"y":90},{"id":"chemo","label":"Chemo, PARPi, radioligands select","x":40,"y":85}],"edges":[{"from":"hsc","to":"mut","type":"activates"},{"from":"mut","to":"chip","type":"activates"},{"from":"chip","to":"mds","type":"activates"},{"from":"chip","to":"cvd","type":"activates"},{"from":"chip","to":"fp","type":"activates"},{"from":"chemo","to":"chip","type":"activates"}],"interventions":["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"]},"route":"/pathways/clonal-haematopoiesis/","neighbours":{"term":[{"id":"ageing-tissue-field-theory","kind":"term","name":"Ageing tissue and clonal fields: cancer as a disease of old tissue","route":"/terms/ageing-tissue-field-theory/"},{"id":"cfdna","kind":"term","name":"Cell-free DNA (cfDNA)","route":"/terms/cfdna/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"epigenetic-progenitor-theory","kind":"term","name":"Epigenetic progenitor theory: cancer without a first mutation","route":"/terms/epigenetic-progenitor-theory/"},{"id":"rejuv-second-from-clone-to-disease","kind":"term","name":"From a clone in the blood to a leukaemia: what is known, and what is done","route":"/terms/rejuv-second-from-clone-to-disease/"},{"id":"secondary-malignancy","kind":"term","name":"Secondary malignancy (therapy-related cancer)","route":"/terms/secondary-malignancy/"},{"id":"tumour-informed-assay","kind":"term","name":"Tumour-informed versus tumour-naive ctDNA assays","route":"/terms/tumour-informed-assay/"},{"id":"vaf","kind":"term","name":"Variant allele frequency (VAF)","route":"/terms/vaf/"}],"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"histiocytoses","kind":"cancer","name":"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms","route":"/cancers/histiocytoses/"},{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"angioimmunoblastic-t-cell-lymphoma","kind":"cancer","name":"Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)","route":"/cancers/angioimmunoblastic-t-cell-lymphoma/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"aml-secondary","kind":"cancer","name":"Secondary and therapy-related acute myeloid leukaemia","route":"/cancers/aml-secondary/"},{"id":"systemic-mastocytosis","kind":"cancer","name":"Systemic mastocytosis","route":"/cancers/systemic-mastocytosis/"}],"technology":[{"id":"rejuv-age-clonal-haematopoiesis-after-therapy","kind":"technology","name":"Clonal haematopoiesis after cancer treatment","route":"/technologies/rejuv-age-clonal-haematopoiesis-after-therapy/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}],"target":[{"id":"asxl1","kind":"target","name":"ASXL1","route":"/targets/asxl1/"},{"id":"b2m","kind":"target","name":"B2M","route":"/targets/b2m/"},{"id":"cd58","kind":"target","name":"CD58","route":"/targets/cd58/"},{"id":"dnmt3a","kind":"target","name":"DNA methyltransferase 3A (DNMT3A)","route":"/targets/dnmt3a/"},{"id":"fyn","kind":"target","name":"FYN","route":"/targets/fyn/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"ppm1d","kind":"target","name":"PPM1D","route":"/targets/ppm1d/"},{"id":"rhoa","kind":"target","name":"RHOA","route":"/targets/rhoa/"},{"id":"tet2","kind":"target","name":"TET2","route":"/targets/tet2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"}],"paper":[{"id":"paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021","kind":"paper","name":"Association of clonal haematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference","route":"/key-papers/paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021/"},{"id":"paper-bolton-nat-genet","kind":"paper","name":"Cancer therapy shapes the fitness landscape of clonal hematopoiesis","route":"/key-papers/paper-bolton-nat-genet/"},{"id":"paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","kind":"paper","name":"Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms","route":"/key-papers/paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021/"},{"id":"paper-jaiswal-chip-nejm-2014","kind":"paper","name":"Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70","route":"/key-papers/paper-jaiswal-chip-nejm-2014/"}],"biomarker":[{"id":"ctdna-tumour-fraction","kind":"biomarker","name":"Circulating tumour DNA fraction (and what a negative plasma result means)","route":"/biomarkers/ctdna-tumour-fraction/"},{"id":"rhoa-g17v","kind":"biomarker","name":"RHOA G17V","route":"/biomarkers/rhoa-g17v/"}],"idea":[{"id":"idea-chip-risk-modifiers","kind":"idea","name":"Which patients' blood clones will become leukaemia after treatment?","route":"/ideas/idea-chip-risk-modifiers/"}],"roadmap":[{"id":"ctdna-tests","kind":"roadmap","name":"ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment","route":"/roadmaps/ctdna-tests/"}]}}