Written in Blood
Clonal Hematopoiesis Almost “Inevitable” in Older Adults
Using whole-genome sequencing
(WGS) data, Florian Zink, from
deCODE genetics/Amgen Inc. in
Reykjavik, Iceland, and co-authors
found that clonal hematopoiesis
(CH) is highly prevalent in older
adults, “trending toward inevitabil-
ity,” according to their report pub-
lished in Blood. Although certain
somatic mutations were strongly
associated with CH, in most cases,
no candidate driver (CD) muta-
tions were present.
“Clonal hematopoiesis is much
more prevalent than previously
reported and appears to be a fate
that awaits anybody who becomes
old enough,” Kári Stefánsson,
MD, the study’s senior author, told
ASH Clinical News. “On one hand,
it may be a normal part of aging.
On the other hand, we show that it
carries clearly increased age-
adjusted risks of all-cause
mortality and hematologic
malignancy.”
The researchers analyzed WGS
data from 11,262 Icelanders who
participated in various disease
projects at deCODE genetics (a
biopharmaceutical research firm).
Patients were excluded from
analyses if they had a diagnosis of
hematologic malignancy before or
within 6 months of blood sampling.
By analyzing the mutational spec-
trum of hematopoietic stem cells
and their clonal descendants, the
researchers were able to diagnose
CH, “irrespective of whether the
predominant clone carries a hema-
tologic malignancy–associated driver
mutation,” Dr. Stefánsson noted.
somatic mutations. The mean vari-
ant allele fraction of the mutations
was 0.17 (range = 0.11-0.20).
Younger participants (<35
years) had a median of three
mosaic somatic mutations, and
the number of mutations climbed
rapidly with age. After applying
a cutoff of >20 mosaic somatic
mutations to classify WGS “outli-
ers” (who were assumed to have
CH), the researchers found that
1,403 participants had CH, for a
percent in those >85 years of age.
To determine the proportion of
patients with CH who carried de-
tectable mosaic somatic mutations,
the authors analyzed 18 CD genes
known to be mutated in myeloid
neoplasia. They observed 286 CD
mutations in 16 of the genes in 246
of the participants. Most of those
participants (n=196) had CD mu-
tations in either DNMT3A (n=93),
TET2 (n=76), ASXL1 (n=25), or
PPM1D (n=18) genes.
“Clonal hematopoiesis is much more
prevalent than previously reported and
appears to be a fate that awaits anybody
who becomes old enough.”
—
KÁRI STEFÁNSSON, MD
More than 3.3 million singleton
single nucleotide polymorphisms
(SNPs) were identified, 146,389 of
which were classified as mosaic
prevalence of 12.5 percent across all
age groups. The frequency of WGS
outliers increased from 0.5 percent
in those <35 years of age to >50
The probability of detection of
these mutations was “strongly de-
pendent” on age, as those patients
were on average 18 years older
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