Clonal Hematopoiesis With Somatic Mutations Increases With Age and Increases Risk of Hematologic Cancer and Mortality
In a study reported in The New England Journal of Medicine, Genovese et al found that clonal hematopoiesis with somatic mutations is increasingly common with greater age and is associated with increased risk of hematologic cancer. The presence of such clonal hematopoiesis in apparently healthy persons may be an early event in development of hematologic cancer.
Study Details
The study 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. 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.
Frequency Increases With Age
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. Among persons with clonal hematopoiesis, the average number of putative somatic mutations increased with age (P < .001).
Risk of Hematologic Cancer, Overall 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 investigators 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.”
Steven McCarroll is the corresponding author for The New England Journal of Medicine article.
The study was funded by the National Human Genome Research Institute and others. For full disclosures of the study authors, visit www.nejm.org.
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