Clonal Hematopoiesis With Somatic Mutations Increases Risk of Hematologic Cancer, Mortality, and Cardiovascular Disease


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Giulio Genovese, PhD

Clonal Hematopoiesis as Risk Factor

In two studies recently reported in The New England Journal of Medicine,1,2 whole-exome sequencing of DNA from peripheral blood cells of individuals unselected for hematologic phenotype showed that clonal hematopoiesis with somatic mutations is increasingly common with increasing age and is associated with increased risk of hematologic cancer and death. One study also observed a significant association with incident coronary heart disease and ischemic stroke.2 The presence of clonal hematopoiesis in apparently healthy persons may be an early event in the development of hematologic cancer.

Genovese et al Study Details

The study reported by Giulio Genovese, PhD, of the Broad Institute of the Massachusetts Institute of Technology in Cambridge, and colleagues involved analysis of data from whole-exome sequencing of DNA in peripheral blood cells from 12,380 Swedish persons unselected for cancer or hematologic phenotypes.1 Participants had a mean age of 55 years (range, 19–93 years) at the time of DNA collection; 6,245 were controls, 4,970 had schizophrenia, and 1,165 had bipolar disorder. Somatic mutations were identified on the basis of unusual allelic fractions. Data from Swedish national patient registers were used to follow outcomes for 2 to 7 years after DNA sampling.

Detectable clonal expansions most frequently involved somatic mutations in three genes—DNMT3A (190 mutations), ASXL1 (35 mutations), and TET2 (31 mutations)—previously implicated in hematologic cancers. Detectable clonal hematopoiesis with candidate driver genes (also including PPMD1 and JAK2 among the most common) was found in only 0.7% of participants aged < 50 years and in 5.7% of participants aged > 65 years.

Overall, clonal hematopoiesis with candidate or unknown driver genes was observed in 0.9% of participants aged < 50 years vs 10.4% of those aged > 65 years.

Risk of Cancer and Mortality

Participants with clonal hematopoiesis were significantly more likely to receive a first diagnosis of hematologic cancer ≥ 6 months after DNA sampling (hazard ratio [HR] = 12.9, P < .001) in analysis adjusting for age and sex. Of 31 participants receiving such a diagnosis, 13 (42%) had clonal hematopoiesis evident in their initial DNA sample.

In analysis adjusting for age and sex, participants with clonal hematopoiesis had significantly increased risk of death (HR = 1.4, P = .03). The reduced overall survival was explained by deaths from cancer and by an association of clonal hematopoiesis with smoking (odds ratio = 2.2, P < .001).

Analysis of bone marrow biopsy specimens from two patients at the time of diagnosis of acute myeloid leukemia revealed that the cancers arose from the initially identified clones.

The researchers concluded: “Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers.”

In an interview with The ASCO Post, Dr. Genovese emphasized, “Despite the fact that the risk of conversion of clonal hematopoiesis to cancer is low—about 1% per year, for a large fraction (~42%) of participants who developed cancer—clonal hematopoiesis preceded clinical diagnosis by several months, sometimes up to 3 years. While there is no effective therapy at the moment for people with clonal hematopoiesis, this observation points to a wide window of time for potential intervention.”

Jaiswal et al Study Details

The study by Siddhartha Jaiswal, MD, PhD, of Brigham and Women’s Hospital, Boston, and colleagues involved analysis of whole-exome sequencing data of DNA from peripheral blood cells from 17,182 persons who were unselected for hematologic phenotypes.2 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.

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 103 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 the variants occurred in the three genes 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).

Cancer, Mortality, Cardiovascular Disease

In analysis adjusting for age, sex, and type 2 diabetes status, the presence of a somatic mutation was associated with an 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 the presence of a mutation (< .001). Somatic mutations were associated with an 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 an 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.

Jaiswal et al 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.” ■

Disclosure: The Genovese et al study was funded by the National Human Genome Research Institute and others. The Jaiswal et al study was funded by the National Institutes of Health and others.

References

1. Genovese G, Kähler AK, Handsaker, RE, et al: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371:2477-2487, 2014.

2. Jaiswal S, Fontanillas P, Flannick J, et al: Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488-2498, 2014.


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