Prediction of risk for myeloid malignancy in clonal hematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia ofundetermined significance (CCUS) are defined by somatic mutation in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) of 0.02 or greater in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults, and defining predictors of MN risk would aid clinical management and research. Analysis of sequenced exomes of healthy U.K Biobank participants (n=438,890) in separate derivation and validation cohorts resulted in the construction of a clonal hematopoiesis risk score (CHRS). Key features in the CHRS were single DNMT3A mutations, high-risk mutations, two or more mutations, a VAF of 0.2 or more, age 65 years or older, having CCUS versus CHIP, and red blood cell indices. CHRS defined low-risk (88.4%), intermediate-risk (10.5%), and high-risk (1.1%) groups. In clinical cohorts, most MN events occurred in high-risk patients with CHIP/CCUS.