Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

Abstract

BACKGROUND The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. METHODS We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. RESULTS Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). CONCLUSIONS Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

“…Such variants are typically present in a proportion of peripheral blood cells at a specific time-point but their frequency can increase or decrease over time and even disappear, suggesting a dynamic pattern of clonal change 1 . Consistent with this data, mutations in genes that are often mutated in myeloid malignancy such as TET2, DNMT3A, ASXL1 and JAK2 have also been described in elderly individuals with no evidence of hematological malignancy [5][6][7][8] . Increasing age is accompanied by changes to the hematopoietic stem cell (HSC) compartment, a process known as myeloid shift, with a bias towards the myeloid lineage at the expense of the lymphoid lineage 9 .…”

Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified

“…On the other hand, somatic mutations in genes associated with myeloid neoplasms (such as DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1, and SF3B1) have been frequently found in aging healthy individuals. [10][11][12]29 MDS-associated somatic mutations and clonal hematopoiesis have been recently reported in near half of patients with aplastic anemia, 30 as well as in patients with idiopathic cytopenias of undetermined significance. 29,31 In the latter, variant allele fractions were comparable with MDS.…”

“…However, this approach has been complicated by reports of frequent somatic mutations in healthy populations of older individuals. [10][11][12] The aim of this multicenter study was to molecularly characterize the cases of idiopathic hypereosinophilic syndrome, and compare them with chronic eosinophilic leukemia, not otherwise specified, as defined by the current World Health Organization criteria. Specifically, we sought to determine whether mutation data would provide clinically meaningful information in these two entities.…”

Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

“…Given that a cancer hotspot panel was used for testing, it is possible that other mutations could be present which were not detectable with the assay used. The presence of low-level somatic mutations in various genes is becoming increasingly interpreted in some clinical contexts [28][29][30] to indicate the presence of an underlying clonal population in the tissue tested; however, the presence of such mutations and/or clonal populations is not necessarily diagnostic of malignancy and may be of uncertain prognostic significance. In each case, the molecular findings must be interpreted in the context of the other clinical and pathologic findings.…”