Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have pronounced elevations in risk of myeloid and lymphoid malignancies (HRs>40), particularly when CHIP and mCAs overlap genomically. Our findings indicate CH co-occurrences are selected for in the aging population and identify CH clones with notable implications for future malignancy risk.