Causes of Clonal Hematopoiesis: a Review

Abstract

Purpose of review: Clonal hematopoiesis (CH) is an age-dependent process detectable using advanced sequencing technologies and is associated with multiple adverse health outcomes including cardiovascular disease and cancer. The purpose of this review is to summarize known causes of CH mutations and to identify key areas and considerations for future research on CH.

Recent findings: Studies have identified multiple potential causes of CH mutations including smoking, cancer therapies, cardiometabolic disease, inflammation, and germline risk factors. Additionally, large-scale studies have facilitated the identification of gene-specific effects of CH mutation risk factors that may have unique downstream health implications. For example, cancer therapies and sources of environmental radiation appear to cause CH through their impact on DNA damage repair genes. There is a growing body of evidence defining risk factors for CH mutations. Standardization in the identification of CH mutations may have important implications for future research. Additional studies in underrepresented populations and their diverse environmental exposures are needed to facilitate broad public health impact of the study of CH mutations.

Keywords: Clonal hematopoiesis; Clonal selection in population; Gene and clonal hematopoiesis risk factor associations; Mutagens; Somatic mutations.

Fig. 1

Model of the proportion and prevalence of clonal hematopoiesis in healthy elderly individuals by gene according to published risk factor data. The top row shows the proportion of clonal hematopoiesis (CH) mutations by gene (e.g., proportion of CH mutations that are in DNMT3A). The bottom row shows the prevalence of CH mutations (e.g., the prevalence of individuals with a mutation in DNMT3A in a given population). Both the top and bottom rows are modeled in a hypothetical population of healthy individuals of age 70 or older. Each column represents a risk factor for CH. A Age: In healthy elderly population, we assumed roughly 50% of CH prevalence at variant allele fraction (VAF) > 0.1%. B Smoking: If all individuals in A were current smokers, loss of function of ASXL1 would have increased two–three times. C Cancer therapy: If all individuals in A were treated by either radiation or chemotherapy, mutations in PPM1D, TP53, and CHEK2 would double. D Hyperlipidemia: If all individuals in A had hyperlipidemia, mutations would have been increased 2- to threefold in TET2 and JAK2. E Chronic inflammation: If all individuals in A had chronic inflammation, 30–50% more mutations would have been observed in DNMT3A and TET2. F Germline variants: If all individuals in A carried one or more germline variants, 20–30% more mutations would have been observed in DNMT3A, TET2, and JAK2