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Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma.
[esophageal adenocarcinoma]
Incidence
of
esophageal
adenocarcinoma
(
EA
)
in
Western
countries
has
increased
markedly
in
recent
decades
.
Although
several
risk
factors
have
been
identified
for
EA
and
its
precursor
,
Barrett
's
esophagus
(
BE
)
,
including
reflux
,
Caucasian
race
,
male
gender
,
obesity
,
and
smoking
,
less
is
known
about
the
role
of
inherited
genetic
variation
.
Frequent
somatic
mutations
in
the
tumor
suppressor
genes
CDKN
2
A
and
TP
53
were
recently
reported
in
EA
tumors
,
while
somatic
alterations
at
9
p
(
CDKN
2
A
)
and
17
p
(
TP
53
)
have
been
implicated
as
predictors
of
progression
from
BE
to
EA
.
Motivated
by
these
findings
,
we
used
data
from
a
genome-
wide
association
study
of
2515
EA
cases
and
3207
controls
to
analyze
37
germline
single
nucleotide
polymorphisms
at
the
CDKN
2
A
and
TP
53
loci
.
Three
CDKN
2
A
polymorphisms
were
nominally
associated
(
P
<
0
.
05
)
with
reduced
risk
of
EA
:
rs
2518720
C
>
T
[
intronic
,
odds
ratio
0
.
90
,
P
=
0
.
0121
,
q
=
0
.
3059
]
,
rs
3088440
G
>
A
(
3
'
UTR
,
odds
ratio
0
.
84
,
P
=
0
.
0186
,
q
=
0
.
3059
)
,
and
rs
4074785
C
>
T
(
intronic
,
odds
ratio
0
.
85
,
P
=
0
.
0248
,
q
=
0
.
3059
)
.
None
of
the
TP
53
single
nucleotide
polymorphisms
reached
nominal
significance
.
Two
of
the
CDKN
2
A
variants
identified
were
also
associated
with
reduced
risk
of
progression
from
BE
to
EA
,
when
assessed
in
a
prospective
cohort
of
408
BE
patients
:
rs
2518720
(
hazard
ratio
0
.
57
,
P
=
0
.
0095
,
q
=
0
.
0285
)
and
rs
3088440
(
hazard
ratio
0
.
34
,
P
=
0
.
0368
,
q
=
0
.
0552
)
.
In
vitro
functional
studies
of
rs
3088440
,
a
single
nucleotide
polymorphism
located
in
the
seed
sequence
of
a
predicted
miR-
663
b
binding
site
,
suggested
a
mechanism
whereby
the
G
>
A
substitution
may
attenuate
miR-
663
b
-mediated
repression
of
the
CDKN
2
A
transcript
.
This
study
provides
the
first
evidence
that
germline
variation
at
the
CDKN
2
A
locus
may
influence
EA
susceptibility
.
Diseases
Validation
Diseases presenting
"tumor suppressor genes"
symptom
cowden syndrome
dedifferentiated liposarcoma
esophageal adenocarcinoma
lymphangioleiomyomatosis
oral submucous fibrosis
pleomorphic liposarcoma
proteus syndrome
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