Premalignant State in Blood Identified

Presence of somatic mutations in haematopoietic stem cells increases likelihood of developing haematological malignancies

medwireNews: Two independent studies published in The New England Journal of Medicine find that clonal expansion of haematopoietic stem cells carrying somatic Mutations is associated with an increased risk of haematological cancers and mortality.

“The data are exciting and provocative, show the power of genomic information for analyzing complex issues of pathogenesis, and will clearly guide future investigations”, says Janis Abkowitz, from the University of Washington, Seattle, USA, in an accompanying comment.

She notes, however, that “because clonal hematopoiesis is common with aging and its prevalence greatly exceeds the age-specific incidence of leukemias, caution is needed when predicting clinical consequences from a cancer-associated Gene mutation in healthy persons.”

Benjamin Ebert, from Harvard Medical School in Boston, Massachusetts, USA, and co-investigators used whole-exome sequencing to examine for variants in 160 candidate genes implicated in myeloid and lymphoid cancer in the peripheral blood DNA of 17,182 individuals from 22 cohorts in Type 2 diabetes association studies and the Jackson Heart Study

Somatic mutations were rare in patients aged less than 40 years, but increased with each decade from the age of 60 years onwards, with frequencies of 5.6%, 9.5%, 11.7% and 18.4% in individuals aged 60 to 69 years, 70 to 79 years, 80 to 89 years and 90 years and above, respectively.

Follow-up data for 3342 patients showed that, after adjusting for age, gender and Type 2 diabetes status, participants with mutations were 11.1 times more likely to be diagnosed with haematological malignancies than those without.

The researchers point out that the absolute risk remained small, however, as “overall, a hematologic cancer developed during the study period in approximately 4% of persons with a mutation”, equating to an overall risk of 0.5% per year.

Patients with somatic mutations also had a significantly higher risk of coronary heart disease, ischaemic stroke and all-cause mortality, than those without detectable mutations, suggesting that the outcomes linked to clonal haematopoiesis “may simply represent a shared consequence of the underlying process of aging”, they write.

Instead of studying candidate genes, the team led by Giulio Genovese, from Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA, looked for somatic mutations in unusual allelic fractions generated from whole-exome sequencing data from 12,380 Swedish patients (6245 controls, 4970 persons with schizophrenia and 1165 persons with bipolar disorder).

They found that clonal haematopoiesis was more common in older rather than younger participants, with an occurrence of 10.4% in individuals aged 65 years and over compared with 0.9% in those younger than 50 years of age.

The majority of somatic mutations occurred in three genes, namely DNMT3A (DNA [Cytosine-5-]-methyltransferase 3 alpha), ASXL1 (additional sex combs-like transcriptional regulator 1) and TET2 (tet methylcytosine dioxygenase 2), which were also the genes observed to be most frequently mutated in the study by Benjamin Ebert et al.

Presence of clonal haematopoiesis was associated with an elevated risk of developing haematological cancer 6 months after DNA collection and of all-cause mortality, at hazard ratios of 12.9 and 1.4, respectively.

Giulio Genovese and co-researchers conclude: “These findings illustrate a way in which DNA sequencing offers information about dynamic processes that progress over the course of a person’s life and are predictive of clinical disease and death.”


Jaiswal S, Fontanillas, P, Flannick, J, et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. N Engl J Med 2014; Advance online publication 26 November. doi:10.1056/NEJMoa1408617

Genovese G, Kähler AK, Handsaker RE, et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. N Engl J Med 2014; Advance online publication 26 November. doi:10.1056/NEJMoa1409405

Abkowitz JL. Clone Wars — The Emergence of Neoplastic Blood-Cell Clones with Aging. N Engl J Med 2014; Advance online publication 26 November. doi: 10.1056/NEJMe1412902

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