Fig. 4. Clonal hematopoiesis across 12,000 donors.

a Blood somatic mutations in the 20 most recurrently mutated genes in the compendium across the metastasis (top) and primary (bottom) cohorts. b Frequency of mutation of CH drivers across the metastasis and primary cohorts. c The 16 most recurrently mutated hotspots in genes in the CH drivers compendium. d Number of donors in the two cohorts with mutations in genes in one or more CH drivers. e Frequency of co-occurring mutations in genes in the CH drivers compendium. Left, Jaccard’s index; right, frequency of gene pairs co-mutation. f Distribution of the rate of hematopoietic mosaic mutations per year (total number of HSC mutations divided by age) across (left) donors bearing a mutation in genes in the CH drivers compendium (N = 420) and (right) donors with no detected mutations in any of these genes (N = 3,247). The horizontal dashed line extends out of the median of the distribution of rate of mutation per year of age of the donors with mutations in at least one CH gene, representing the donors in the second group that are considered to be cases of clonal hematopoiesis (see next panel). In the boxplots, the box represents the second and third quartiles, separated by a line indicating the median; the whiskers represent the minimum and maximum of the distribution excluding outliers. The two distributions were compared using the two-tailed Wilcoxon-Mann-Whitney test. g Number of donors (above the bars) in the metastasis cohort with clonal hematopoiesis recognizable using different criteria (cumulative bars). First, donors with mutations (detected in the germline calling) in any of the 15 known CH genes; second, donors with variants in known CH genes identified in reverse calling; third, donors with mutations in CH genes discovered across the primary or metastasis cohorts; fourth, donors with mutations in CH genes discovered in the targeted cohort; fifth, donors with no mutation in any gene within the compendium of CH drivers, but with more hematopoiesis mutations per year of age of the donor than the median rate of hematopoiesis mutations across donors in the four previous groups. Source data for panels a, b, c, d, e, f and g are provided as Source Data files.