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Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.
[cowden syndrome]
PTEN
is
a
well-described
predisposition
gene
for
Cowden
syndrome
(
CS
)
,
a
familial
cancer
syndrome
characterized
by
a
high
risk
of
breast
and
other
cancers
.
KLLN
,
which
shares
a
bidirectional
promoter
with
PTEN
,
causes
cell
cycle
arrest
and
apoptosis
.
We
previously
identified
germline
hypermethylation
of
the
KLLN
promoter
in
37
%
of
PTEN
mutation
-negative
CS
/
CS
-like
(
CSL
)
patients
.
Patients
with
germline
KLLN
hypermethylation
have
an
increased
prevalence
of
breast
and
renal
cancers
when
compared
with
PTEN
mutation
carriers
.
We
have
consequently
sought
to
identify
and
characterize
germline
KLLN
variants
/
mutations
in
CS
/
CSL
and
in
apparently
sporadic
breast
cancer
patients
.
KLLN
variants
in
CS
/
CSL
patients
are
rare
(
1
of
136
,
0
.
007
%
)
.
Interestingly
,
among
438
breast
cancer
patients
,
13
(
3
%
)
have
germline
KLLN
variants
when
compared
with
none
in
128
controls
(
P
=
0
.
049
)
.
Patients
with
KLLN
variants
have
a
family
history
of
breast
cancer
when
compared
with
those
without
(
P
=
0
.
02
)
.
We
demonstrate
that
germline
KLLN
variants
dysregulate
the
cell
cycle
at
G
2
.
Of
24
breast
carcinomas
analyzed
,
3
(
13
%
)
have
somatic
KLLN
hemizygous
deletions
,
with
somatic
loss
of
the
wild-
type
allele
in
a
patient
with
germline
KLLN
p
.
Leu
119
L
eu
.
Of
452
breast
carcinomas
in
The
Cancer
Genome
Atlas
project
,
93
(
21
%
)
have
KLLN
hemizygous
or
homozygous
deletions
.
This
is
the
first
study
to
associate
germline
KLLN
variants
with
sporadic
breast
cancer
and
to
recognize
somatic
KLLN
deletions
in
breast
carcinomas
.
Our
observations
suggest
that
KLLN
may
be
a
low
penetrance
susceptibility
factor
for
apparently
sporadic
breast
cancer
.
Diseases
Validation
Diseases presenting
"breast cancer"
symptom
acute rheumatic fever
aromatase deficiency
carcinoma of the gallbladder
child syndrome
cowden syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
esophageal squamous cell carcinoma
junctional epidermolysis bullosa
kindler syndrome
liposarcoma
lymphangioleiomyomatosis
oral submucous fibrosis
proteus syndrome
severe combined immunodeficiency
systemic capillary leak syndrome
von hippel-lindau disease
waldenström macroglobulinemia
werner syndrome
wiskott-aldrich syndrome
This symptom has already been validated