In the Journals

Age-related clonal hematopoiesis increased risk for hematologic malignancies

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November 26, 2014

Somatic mutations that led to clonal outgrowth of hematopoietic cells occurred more frequently in older patients and were associated with an increased risk for hematologic malignancies, according to results of two studies published in The New England Journal of Medicine.

The first analysis — conducted by Siddhartha Jaiswal, MD, PhD, clinical fellow in pathology at Massachusetts General Hospital, and colleagues — included 17,182 adults who were unselected for hematologic phenotypes (median age, 58 years). A majority of these participants (n=15,801) were enrolled in type 2 diabetes association studies, and 1,381 were enrolled in the Jackson Heart Study.

Researchers conducted whole-exome sequencing of DNA from peripheral blood cells and identified 805 mutations in 73 genes from 746 of the participants. The most commonly mutated genes were DNMT3A (403 variants), TET2 (72 variants) and ASXL1 (62 variants).

Participants aged 90 to 108 years had the highest frequency of mutations (18.4%), whereas somatic mutations were observed in 11.7% of participants aged 80 to 89 years, 9.5% of participants aged 70 to 79 years and 5.6% of participants aged 60 to 69 years. Researchers noted somatic mutations were rare in participants younger than 40 years.

Researchers conducted additional analyses on 3,342 participants, 4% of whom (n=134) had a somatic mutation. Sixteen participants developed hematologic malignancies after a median follow-up of 95 months; five of whom (31%) had a somatic mutation.

Results of a meta-analysis adjusted for age, sex and type 2 diabetes indicated participants who harbored a somatic mutation were at an increased risk for hematologic malignancies (HR=11.1; 95% CI, 3.9-32.6). Using these data, researchers found the risk for a hematologic malignancy with a somatic mutation was approximately 0.5% per year.

Somatic mutations also were associated with an increased risk for all-cause mortality (HR=1.4; 95% CI, 1.1-1.8). However, researchers noted the risk for all-cause mortality may have been linked to the increased risks for incident coronary heart disease (HR=2; 95% CI, 1.2-3.5) and ischemic stroke (HR=2.6; 95% CI, 1.3-4.8) also observed in participants with somatic mutations.

In the second study, Giulio Genovese, PhD, of the Stanley Center for Psychiatric Research at the Broad Institute of the Massachusetts Institute of Technology, and colleagues evaluated the DNA in peripheral blood cells from 12,380 Swedish adults using whole-exome sequencing (mean age, 55 years). The population consisted of 6,245 control participants, 4,970 adults with schizophrenia and 1,165 adults with bipolar disorder.

Researchers identified 3,111 putative somatic mutations, the most common of which occurred in the DNMT3A, ASXL1, TET2 and PPM1D genes. A greater proportion of participants older than 65 years vs. younger than 50 years had clonal hematopoiesis with candidate or unknown drivers (10.4% vs. 0.9%).

Researchers then evaluated data from Swedish national patient registers to follow the participants for 2 to 7 years.

Clonal hematopoiesis was significantly associated an increased risk for developing a hematologic cancer 6 months or later after DNA sampling (HR=12.9; 95% CI, 5.8-28.7). Clonal hematopoiesis also was associated with an increased risk for death (HR=1.4; 95% CI, 1-1.8).

Researchers conducted additional bone marrow analyses from two patients who developed acute myeloid leukemia. Results showed their cancers developed from clones present in their earlier DNA sample.

Despite the association between clonal hematopoiesis and the risk for hematologic malignancies observed in both studies, researchers cautioned these data may not support population-based screening.

“At this time, it would be premature to genetically screen healthy persons for the presence of a somatic clone, since the positive predictive value for the presence of cancer or for the development of cancer is low,” Jaiswal and colleagues wrote. “Further studies will be needed to definitively assess the natural history of clonal hematopoiesis.”

Genovese and colleagues included a similar caveat.

“Our results raise the question of whether DNA sequencing of blood samples on a regular basis could enable early detection of blood cancers. On the basis of the current data, we believe that such an approach would be premature,” Genovese and colleagues wrote. “In the future, however, it may be possible to refine our DNA analysis in order to develop strategies for early detection and even prevention of hematologic cancer. DNA analysis will offer three important capabilities: the ability to ascertain high-risk states, the ability to monitor the progression or remission of these states, and the ability to ascertain follow-on, transforming mutations before clinically apparent illness.”

For more information:

  • Genovese G. N Engl J Med. 2014;doi:10.1056/NEJMoa1409405.
  • Jaiswal S. N Engl J Med. 2014;doi:10.1056/NEJMoa1408617.

Disclosure: See the studies for a list of the researchers’ relevant financial disclosures.

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