Age-Related Clonal Hematopoiesis Associated With Increased Risk of All-Cause Mortality, Heart Disease, and Stroke, as Well as Blood Cancer
In a study reported in The New England Journal of Medicine, Jaiswal et al found somatic mutations associated with hematologic cancers at increasing frequency with increasing age, with presence of the mutations being associated with increased risk of hematologic cancers, all-cause mortality, incident coronary heart disease, and ischemic stroke.
Study Details
The study involved analysis of whole-exome sequencing data of DNA from peripheral blood cells from 17,182 persons who were unselected for hematologic phenotypes. The somatic mutations sought were from among previously identified single nucleotide variants and small insertions or deletions in 160 genes recurrently mutated in hematologic cancer.
The study sample was selected from 22 population-based cohorts in three consortia (T2DGENES, GoT2D, and SIGMA T2D). DNA obtained from individual cohorts was further processed at the Broad Institute of Harvard and the Massachusetts Institute of Technology.
Participants had a median age of 58 years (range = 19–108 years), 8,741 were women, and 7,860 had type 2 diabetes.
Age-Related Frequency
Somatic mutations were very rare in persons aged < 40 years, being found in 0 (0%) of 240 aged 20 to 29 years, 1 (0.1%) of 855 aged 30 to 39 years, 50 (1.7%) of 2,894 aged 40 to 49 years, 138 (2.5%) of 5,441 aged 50 to 59 years, 282 (5.6%, 95% confidence interval [CI] = 5.0%–6.3%) of 5,002 aged 60 to 69 years, 219 (9.5%, 95% CI = 8.4%–10.8%) of 2,300 aged 70 to 79 years, 37 (11.7%, 95% CI = 8.6%–15.7%) of 317 aged 80 to 89 years, and 19 (18.4%, 95% CI = 12.1%–27.0%) of those aged ≥ 90 years. As noted by the investigators, these rates greatly exceed the incidence of clinically diagnosed hematologic cancer in the general population.
The majority of variants occurred in DNMT3A (403 variants), TET2 (72 variants), and ASXL1 (62 variants). Among persons aged ≥ 60 years, men were more likely to have a detectable mutation (odds ratio [OR] = 1.3, P = .005).
Increased Risk of Hematologic Cancer, Mortality, Cardiovascular Disease
In analysis adjusting for age, sex, and type 2 diabetes status, the presence of a somatic mutation was associated increased risk of hematologic cancer (hazard ratio [HR] = 11.1, P < .001).
In a model adjusted for age, sex, and type 2 diabetes status, presence of a mutation was associated with increased all-cause mortality (HR = 1.4, P = .02); Kaplan-Meier analysis among persons aged ≥ 70 years also showed increased risk of death with presence of a mutation (P < 0.001). Somatic mutations were associated with increased risk of diabetes after adjustment for confounding factors (OR = 1.3, P < .001), with individuals with diabetes being slightly more likely to have such mutations in every age group. In multivariable analysis including age, sex, type 2 diabetes status, systolic blood pressure, and body mass index as covariates, presence of a somatic mutation was associated with increased risk of incident coronary heart disease (HR = 2.0, P = .02) and ischemic stroke (HR = 2.6, P = .003).
Targeted sequencing of blood cell DNA obtained 4 to 8 years after the initial DNA collection for 17 mutations in 13 persons showed that the originally detected mutations were still present in all cases.
The investigators concluded: “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.”
Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School, is the corresponding author for The New England Journal of Medicine article.
The study was funded by the National Institutes of Health and others. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
