Nature Communications,
Год журнала:
2016,
Номер
7(1)
Опубликована: Авг. 22, 2016
Abstract
Clonal
haematopoiesis
is
thought
to
be
a
rare
condition
that
increases
in
frequency
with
age
and
predisposes
individuals
haematological
malignancy.
Recent
studies,
utilizing
next-generation
sequencing
(NGS),
observed
haematopoietic
clones
10%
of
70-year
olds
rarely
younger
individuals.
However,
these
studies
could
only
detect
common
clones—>0.02
variant
allele
fraction
(VAF)—due
the
error
rate
NGS.
To
identify
characterize
clonal
mutations
below
this
threshold,
here
we
develop
methods
for
targeted
error-corrected
sequencing,
which
enable
accurate
detection
as
0.0003
VAF.
We
apply
study
serially
banked
peripheral
blood
samples
from
healthy
50–60-year-old
participants
Nurses’
Health
Study.
observe
haematopoiesis,
frequently
harbouring
DNMT3A
TET2
,
95%
studied.
These
are
often
stable
longitudinally
present
multiple
compartments,
suggesting
long-lived
stem
progenitor
cell
origin.
New England Journal of Medicine,
Год журнала:
2016,
Номер
374(23), С. 2209 - 2221
Опубликована: Июнь 8, 2016
Recent
studies
have
provided
a
detailed
census
of
genes
that
are
mutated
in
acute
myeloid
leukemia
(AML).
Our
next
challenge
is
to
understand
how
this
genetic
diversity
defines
the
pathophysiology
AML
and
informs
clinical
practice.
New England Journal of Medicine,
Год журнала:
2017,
Номер
377(2), С. 111 - 121
Опубликована: Июнь 21, 2017
Clonal
hematopoiesis
of
indeterminate
potential
(CHIP),
which
is
defined
as
the
presence
an
expanded
somatic
blood-cell
clone
in
persons
without
other
hematologic
abnormalities,
common
among
older
and
associated
with
increased
risk
cancer.
We
previously
found
preliminary
evidence
for
association
between
CHIP
atherosclerotic
cardiovascular
disease,
but
nature
this
was
unclear.
Science,
Год журнала:
2015,
Номер
348(6237), С. 880 - 886
Опубликована: Май 22, 2015
How
somatic
mutations
accumulate
in
normal
cells
is
central
to
understanding
cancer
development
but
poorly
understood.
We
performed
ultradeep
sequencing
of
74
genes
small
(0.8
4.7
square
millimeters)
biopsies
skin.
Across
234
sun-exposed
eyelid
epidermis
from
four
individuals,
the
burden
averaged
two
six
per
megabase
cell,
similar
that
seen
many
cancers,
and
exhibited
characteristic
signatures
exposure
ultraviolet
light.
Remarkably,
multiple
are
under
strong
positive
selection
even
physiologically
skin,
including
most
key
drivers
cutaneous
squamous
cell
carcinomas.
Positively
selected
were
found
18
32%
skin
at
a
density
~140
driver
centimeter.
observed
variability
landscape
among
individuals
sizes
clonal
expansions
across
genes.
Thus,
aged
patchwork
thousands
evolving
clones
with
over
quarter
carrying
cancer-causing
while
maintaining
physiological
functions
epidermis.
Journal of the National Comprehensive Cancer Network,
Год журнала:
2018,
Номер
16(3), С. 310 - 320
Опубликована: Март 1, 2018
Ductal
carcinoma
in
situ
(DCIS)
of
the
breast
represents
a
heterogeneous
group
neoplastic
lesions
ducts.
The
goal
for
management
DCIS
is
to
prevent
development
invasive
cancer.
This
manuscript
focuses
on
NCCN
Guidelines
Panel
recommendations
workup,
primary
treatment,
risk
reduction
strategies,
and
surveillance
specific
DCIS.
Cell,
Год журнала:
2017,
Номер
171(5), С. 1029 - 1041.e21
Опубликована: Окт. 19, 2017
Cancer
develops
as
a
result
of
somatic
mutation
and
clonal
selection,
but
quantitative
measures
selection
in
cancer
evolution
are
lacking.
We
adapted
methods
from
molecular
applied
them
to
7,664
tumors
across
29
types.
Unlike
species
evolution,
positive
outweighs
negative
during
development.
On
average,
<1
coding
base
substitution/tumor
is
lost
through
with
purifying
almost
absent
outside
homozygous
loss
essential
genes.
This
allows
exome-wide
enumeration
all
driver
mutations,
including
known
carry
∼4
substitutions
under
ranging
<1/tumor
thyroid
testicular
cancers
>10/tumor
endometrial
colorectal
cancers.
Half
occur
yet-to-be-discovered
With
increasing
burden,
numbers
mutations
increase,
not
linearly.
systematically
catalog
genes
show
that
vary
extensively
what
proportion
drivers
versus
passengers.
Science,
Год журнала:
2017,
Номер
355(6327), С. 842 - 847
Опубликована: Янв. 20, 2017
Human
aging
is
associated
with
an
increased
frequency
of
somatic
mutations
in
hematopoietic
cells.
Several
these
recurrent
mutations,
including
those
the
gene
encoding
epigenetic
modifier
enzyme
TET2,
promote
expansion
mutant
blood
This
clonal
hematopoiesis
correlates
risk
atherosclerotic
cardiovascular
disease.
We
studied
effects
Tet2-mutant
cells
atherosclerosis-prone,
low-density
lipoprotein
receptor-deficient
(Ldlr-/-)
mice.
found
that
partial
bone
marrow
reconstitution
TET2-deficient
was
sufficient
for
their
and
led
to
a
marked
increase
plaque
size.
macrophages
exhibited
NLRP3
inflammasome-mediated
interleukin-1β
secretion.
An
inhibitor
showed
greater
atheroprotective
activity
chimeric
mice
reconstituted
than
nonchimeric
These
results
support
hypothesis
TET2
play
causal
role
atherosclerosis.
