CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Dr. Ebert
Dr. Ebert’s group sought to find out whether there are point mutations that lead to clonal hematopoiesis in the general population. To do this they examined whole exome sequencing data from the peripheral blood of more than 17,000 people; the data were acquired for studies investigating the genetic basis of diabetes or cardiovascular disease.
They found that the incidence of clonal hematopoiesis of indeterminate potential was “surprisingly high” in the elderly, Dr. Ebert said. By age 70, approximately 10 percent of individuals had clonal hematopoiesis—one dominant clone that makes up between 20 percent and 80 percent of their peripheral blood and that contains a mutation with one of the known driver genes (Jaiswal S, et al. N Engl J Med. 2014;371:2488–2498). Dr. Ebert called this “likely a conservative estimate.”
Corresponding with Dr. Goodell’s work, this analysis showed that the DNMT3A gene was most frequently mutated, by a large margin. In second place were TET2 mutations. Giving a nod to Dr. Goodell’s work, Dr. Ebert said, “In mice these mutations cause clonal expansion in hematopoietic stem cells without symptoms of disease.”
Among people with CHIP, a large fraction of cells in the blood bear the same mutation—a mean of 24 percent of blood peripheral cells, or, as Dr. Ebert said, “a sizable clone.” This is different from the discovery of rare BCR/ABL clones in some individuals that may be transient. An additional sample was available for analysis from a later time. All variants persisted during the subsequent four to eight years, and in a few cases a second mutation was acquired during follow-up.
As one would predict, the risk of a hematologic malignancy was increased in subjects with clonal hematopoiesis. They had about a 10-fold risk over 150 months. For those with larger clones, the risk was increased 50-fold. Dr. Ebert said that CHIP can be seen as a premalignant state much like monoclonal gammopathy of unknown significance, in that the odds of progression to overt neoplasia are 0.5 percent to one percent per year.
Clonal hematopoiesis was associated with significantly decreased survival; it increased overall mortality about 40 percent. This was not due to a higher risk of cancer but to an increased probability of developing coronary heart disease and ischemic stroke—“a surprising finding,” Dr. Ebert said.
Similar results from a number of other groups at roughly the same time verified the findings of Dr. Ebert and his collaborators.
One clinical implication of the findings, he said: “We need to make sure that individuals coming in for rule-out MDS aren’t misdiagnosed by finding DNMT3A mutations.”
A key question is, When do we say that CHIP has progressed to MDS? “Our challenge now,” Dr. Ebert said, “is that we don’t have any consensus for diagnostic criteria for drawing cutoffs based on mutant allele fractions and number of mutations.”
When, he asked, would you do a CHIP screen? With no intervention to alter outcomes, he said, “there is no rationale for wide-scale screening.”
Dr. Goodell calls the finding of CHIP “transformative.”
“To me, as a stem cell biologist who has worked on HSC for 25 years, I am astounded by the implications of the fact that when we are old we might end up relying on only a handful of different stem cells.”
If these findings are borne out, she says, “Pathologists will end up testing for this. It may be related to the aging phenomenon. Right now we are 10 years away from that.”n
William Check is a writer in Ft. Lauderdale, Fla.
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