Vol.
4, 671-676,
Marc/i
1998
Clinical
Prognostic
Value
of Chorionic
in Human
Breast
Carcinoma’
Ivan
Bi#{232}che,2 Vladimir
Thierry
Poynard,
Dominique
Yves
Bellet,
Michel
Lazar,2
Gonadotropin
Catherine
Nogu#{232}s,
Lidereau,
and
(P
Vidaud3
f3 subunit
of human
chorionic
encoded
by six genes,
which
previously
showed
that, whereas
sively expressed
in normal
breast
II genes
let,
was associated
a simple
and
a negative
is
dian
tumor
with
and
grade,
and
Patients
mRNA
(P
=
lymph
with
had
node
and
is composed
nated
a
had
is
and
invasive
long-term
was
in 48 (48.5%)
index
was
status
(me-
for
the
steroid
index
shorter
survival
receptor
in primary
metastasis-free
(P
=
0.038)
after
( 1 ).
have
growth,
10/20/97;
of publication
revised
12/31/97;
accepted
of this article
were
but
mas
says,
2
These
authors
3
To whom
pour Ia Recherche
contributed
requests
GCnetique
Mol#{233}culaire, JE DRED
ceutiques
et Biologiques
de Paris,
Paris,
France.
that
also
(3).
as
However,
status.
mRNA
tumor
ent
given
in nontrophoblastic
subunit
surgery,
six
genes,
1;
Ref.
embryonically
normal
is composed
two
of
145
amino
acids
are
allelic
(38,
of which
1 1). All
19 (12).
are contained
Three
other
Surprisingly,
in part by the
in
malignant
normal
breast
CG36),
whereas
about
we
cells
half
the
but
tissues
were
also
were
malignant
breast
samples
able
in
to detect
normal
found
located
at least
CG3
33 or
on chromoin this
cluster:
and
mRNAs
(1 1).
to express
the
1 1 ). The
by
proteins,
cells
as
of differ-
( 10,
cluster
of
CG3
37, or 36 and
transformation
with
to assess
is coded
35,
are also
be
such
tissues
in a single
genes
also
tumors,
tissue
and
solid
carcino-
of immunoas-
cancer
breast
a-fetopro-
certain
could
analysis
and
including
intact
related
cervical
solid
RT-PCR
not
and
with
studies
other
germ
epithelial
other
back of sensitivity
to
of
and
(but
and
fluids
indicator
antigen
used
origins,
or body
subunit
of patients
regard
embryo
functions,
of nongonadal
CG3-based
We recently
the
CG3
pancreas,
the
with
histological
survival
two
bladder,
whether
relevance
cancer.
like
of
of the growth
of tissue
(carcinoembryonic
it is unclear
breast
range
for the monitoring
such
of
in trophoblastic
of free
CG
is essential
regulation
only
four
stages
endocrine
studies
levels
biomarkers
hormone
of CG as a significant
in a wide
could,
first
maintenance
in paracrine
desigthe
the
LH
not only
Interestingly.
only
CG37
was
associated
emergence
of the
(or
in
CG3
sur le Cancer.
equally
for reprints
family
thyrotropin
to
very
classical
not
Serum
be useful
clinical
payment
of page charges.
This article
must therefore
be hereby
marked
advertisement
in accordance
with
18 U.S.C.
Section
1734 solely
to
indicate this fact.
I This
work was supported
by the Ligue
Nationale
de Lutte Contre
le
Cancer,
the Comit#{233}sRegionaux
des Hauts de Seine et des Yvelines,
and
the Association
pa-
specificity.
the
of this
these
3 subunit
CGa)
in
and
Besides
transformation,
or free
12/31/97.
defrayed
con-
subunits,
biological
cells
immunochemical
(2-9).
bound
production
to the
tumors
tein),
99
trophoblast
and
is common
the 31 and 32 genes,
encoding
unidentified
(or 34) gene, encoding
the LH
subunit.
Received
may
cancer
hormone
subunit
confers
to be involved
cell types (1).
malignant
CG
a
development,
pointed
some
The costs
index
hormone,
noncovalently
The
the 3 subunit
pregnancy.
CG appears
of various
as-
of the
significantly
parameters,
including
size,
histopathological
or
CG117
not
with
respectively).
breast
to a glycoprotein
Consistent
cancer
primary
outcome
together
0.009,
the CG117
follicle-stimulating
by
pregnancy.
during
belongs
3
synthesized
cell
tissues
index
that
P
of high-risk
of two
and
Numerous
gona-
breast
CG117
unilateral
positive
significantly
and overall
0.014)
LH,
tumors
of the
prognostic
tumor
a positive
CG4
malignancies,
The
standard
macroscopic
Human
includes
measures
consistently
cancer
known
9 years).
index
was
samples.
that
0 to 100%.
of 99
with
designed
of chorionic
tissues
significance
patients
mRNA
sociated
clinical
from
(Beb-
We
assay)
types
whereas
in a series
follow-up,
The CG117
both
breast
index,
ranging
cancer
CG117
II over
prognostic
investigated
breast
(the
1997).
indicate
0.016),
(P
and
0.027
identification
also
hormones,
117:
We
transformation
516-523,
Normal
CG117
indexes
The
test
of type
I mRNAs.
showed
57:
robust
the percentage
dotropin
Res.,
survival
mubtivarisurvival
INTRODUCTION
type I genes
were exclutissues,
expression
of type
with malignant
D., et a!. Cancer
The prognostic
tients.
he categorized
into two types based on a sequence
change at codon
GCC for the type I and GAC for the type II genes.
findings
to the
index.
index persisted
in Cox
both
for metastasis-free
(P
671
Research
Transcripts
with a negative
overall
status
These
gonadotropin
can
and
node
tribute
ABSTRACT
The
to patients
0.008)
=
lymph
Laboratoire
de G#{233}n#{233}tique
Mol#{233}culaire [I. B., Y. 0., M. V.] and Unite
de Recherche
Associ#{233}e 1484 Centre
National
de la Recherche
Scientifique
[V. L., T. P., D. B.], Facult#{233}des Sciences
Pharmaceutiques
et Biologiques
de Paris, 75006
Paris;
and
Laboratoire
d’Oncog#{233}n#{233}tique[I. B., R. L.] and D#{233}partement de
Statistiques
M#{233}dicales [C. N.], Centre
Ren#{233}
Huguenin,
9221 1 Saint Cloud,
France
potentially
compared
significance
of the CG117
ate regression
analysis,
Giovangrandi,
Rosette
Gene
Cancer
to this
should
work.
be addressed,
at Laboratoire
351, Facult#{233}des Sciences
4 Avenue
de l’Observatoire,
de
Pharma-
75006
4
The
abbreviations
used
verse transcriptase-PCR;
free survival;
OS, overall
are: LH, luteinizing
CO. chorionic
survival.
hormone;
gonadotropin:
MFS.
RT-PCR.
metastasis-
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 1998 American Association for Cancer
Research.
re-
672
Prognostic
Value
of CG3
in Breast
Cancer
serving
IPrimary
breast
as a control
index
ranges
genes
genes
are
Here,
oftoCal RNA
the
Reverse transcription
with ohgodT
the
0%,
other
types
in tissues
of CG3
transcripts.
to 100%,
17 index
cancer
in tissues
an investigation
in a series
patients
significance
in which
The
only
type
I CG3
in which
only
type
II
transcribed.
we present
CG1
breast
+
from
are transcribed,
CG3
Extraction
for
tumor
of CO
of the prognostic
of 99 unilateral
with
known
1 1 7 index
value
invasive
long-term
of
primary
outcome.
as a prognostic
factor
The
is discussed.
I cDNA
PATIENTS
First round of PCP
specific pomers (COt
wrih CGf
.
CG2)
AND
Patients
mens
were
r
CG2
I
range,
following
CG2]
IcI
cancer
plete
o
-
had
were
adjuvant
indexj
is extracted
and reverse-transcribed
before
from
specific
am-
plification
of CG3 cDNAs
using CG1 and CG2 primers.
Primers
were
designed
specifically
to avoid amplification
of LH3 cDNA
and contaminant genomic
DNA
(1 1). A second
round
of PCR amplification
was
performed
to enable
the distinction
between
type I and type II CG3
genes:
the common
primer
CG2 associated
with the CG3 allele-specific
primer
labeled
with TET amplifies
type I CG3 PCR products,
whereas
the CG4 allele-specific
primer
labeled
with FAM amplifies
type II CG[3
PCR products.
The resulting
TET and FAM peak areas,
representative
of type I and type II CG3 transcripts,
were recorded
on a 373A
DNA
sequencer
(Perkin-Elmer).
The CG1 17 index is defined
as the percentage of type II CG3 mRNAs
among
type I and type II CG3 mRNAs.
and
transcriptionally
active
developed
a test
guishes
those
based
on
CG3
the
existence
1). This
indicates
genes
of an
assay
the
among
efficiency,
expressed
and
as
A-to-C
percentage
a
do
ratio,
with
assay,
Finally,
35,
change
“CG1
transcribed
by
both
we
3 months
was
type
was
bution
and/or
each
because
the
type
of
transcript
CG3
II
results
of
consisting
of
first
curred
deaths
(range,
I .0-16.2
1996.
relapse
had
had
17),
(not
tumors).
considered
as relapse
type
and
of
steroid
of positive
surgery.
The
according
to
Richardson
as
malignancy
the
by
the
Extraction.
Patients
were
placed
were
included
preparation
histological
Total
method
electrophoresis
and
for
Factors.
The hisof each
at the
carcinomas
of
receptors
(14),
a detection
threshold
study
more
after
surgery,
until
extraction
if the tumor
than
60%
and
were
for
in this
was
Bloom
Organization
contained
tumor
established
progesterone
nitrogen
S
oc-
of the 32
grading
Immediately
8
and
cancers
European
in liquid
this
(distri-
All but two
infiltrating
with
next
as follows:
invasive
were
histoprognostic
(I 3). Estrogen
described
of
the
4 both,
status
nodes
All
scans,
and
follow-up
date
was
receptor
axiblary
for
metastases,
cancer.
Prognostic
hormone
26).
relapsed
patients
events).
a
=
bone
median
cutoff
second
re-
(mainly
radiography
6 months
patients
Three
(ii
chest
The
25
were related
to breast
Evaluation
of “Classical”
scored
RNA
years).
their
had
cyclosphospha-
or both
every
among
of
patients
and
Forty-two
events
patients
as part
and routine
year.
tumors
chemotherapy
(n
recurrences,
breast
RNA
type
index
the
regional
contralateral
samples
type
I and
to influence
the reliability
and quality,
amplification
this
26
Fifty-four
high-risk
January
of first
local
at codon
17 index”),
by
or
nodes
factors
are
undergone
and
therapy
Sixty-two
therapy
and Treatment
for Cancer
fmollmg
cytosolic
protein.
or 39),
33
All
total
Seventy-seven
carcinomas.
examination
for
9 years
analysis
sayed
distin-
(37 or 36)
genes
(the
to be
which
(p8,
nucleotide
of mRNAs
affect
cells.
I CG3
an index
known
quantity
not
are known
genes
transcribed
factors
(RNA
17
type
II CG3
provides
mRNAs
so on)
CG1
from
by type
genes
trophoblastic
the
transcribed
II CG3 genes. Most
PCR-based
assays
are
in normal
transcribed
1 17 (Fig.
39); the batter
designated
mRNAs
from
which
133 (or
dissection,
com-
data.
of
prognostic
women
had
year, and then annually.
Liver
scintigraphy,
mammograms
were carried
out annually.
The
time
35,
number
methotrexate,
hormone
a physical
and the number
38,
and
either
(mean
radiation
therapy,
19),
=
tological
genes
included);
surgery;
undergone
node
of fluorouracil,
n
every
tissue
nodes
clearance.
ductal
treatment.
underwent
RNA
lymph
postoperative
combination
Total
had
dissection
axilbary
infiltrating
received
mide;
tumor
the
no other
and biological
main
classifying
1 . Seventy-three
and
with
(77.8%)
373A DNA sequencer
breast
57.6
met
carcinoma;
before
study
node
16). The
in Table
mastectomy
ceived
frozen
Ren#{233}
age,
period
(supraclavicular
histological,
this
lymph
locoregional
CO 1 17 assay.
this
breast
or chemotherapy
for
axillary
lumpectomy
Lti11cG
________I
typeICGC
the
(mean
during
speci-
Center
-
117
of
tumor
at the
patients
unilateral
of clinical,
selected
simple
Principle
These
or metastasis
collection
patients
FAM
1
treated
treated
primary
therapy
examined,
presented
Fig.
years)
criteria:
partial
ICGII7
patients
to 1988.
34-83
no radiation
Second round of PCR using
allele-specific
TEr-labelled
CG3,
and FAM-labelled
CG4 primers
I
1979
breast
Primary
99
34755
CG1
LH
o
from
from
primary
I
Treatment.
obtained
Huguenin
years;
METHODS
and
as-
Research
of 10
the
tumor
of RNA.
sample
used
of tumor
for
cells
(by
analysis).
RNA
(15).
was
The
prepared
quality
through
using
of RNA
denaturing
the acid-phenol
guanidium
samples
was
determined
agarose
gels,
staining
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 1998 American Association for Cancer
Research.
by
with
Clinical
Table
I
Characteris
tics
of the 9 9 patients
and
re lationship
to
MFS
and
No. of
events
37 (37.4)
62 (62.6)
14
28
81.1
76.5
11 (11.8)
50 (53.8)
32 (34.4)
3
23
15
100
73.4 (6.3)
77.0 (7.6)
30.0(23.9)
47.7 (8.3)
44.4 (10.1)
Lymph
31 (31.6)
67 (68.4)
7
35
76.7
78.6
76.7
37.4
64 (66.0)
29
79.1 (5.2)
40.2 (8.6)
33 (34.0)
13
75.0
54.2
The
‘,
Kaplan-Meier
number
(7.7)
(5.1)
(7.7)
60 (61.9)
28
76.2 (5.6)
37 (38.1)
14
80.5
63 (65.6)
33 (34.4)
26
15
78.7
75.2
for each
parameter
does
classification.
progesterone
PR,
and
visualization
Total
RNA
extraction
(1 jig)
and
according
RNA
l8S
yield
PCR
common
17
transcription
(6.6)
(5.3)
(7.6)
49.8
39.0
(7.8)
(12.3)
not
necessarily
equal
and
28S
RNA
was quantified
was
50 mM
KC1, and 2.5
a Perkin-Ebmer
mix,
CG1
units
ofTaq
reactions
9600
were
DNA
thermal
cycler.
allele-specific
TET
nested
and FAM,
were
carried
of each
of the common
3 mM
MgCb2,
2 units
of the
Elmer).
Each
tive
Stoffeb
primers
out
primer
10 msi
primer
200
jiM
(pH
(Perkin-
out in 30 sequen-
CG2,
two
final
jiM
(pH
of Taq
(8.7)
(12.6)
4
26
90.3
87.9
(5.3)
(4.0)
86.0
51.0
(6.6)
(7.7)
20
90.5 (3.7)
62.7 (7.1)
10
84.5
(6.4)
54.4
(12.4)
22
8
88.2
89.0
(4.2)
(5.2)
51.6
73.2
(8.5)
(8.9)
18
12
87.0
90.8
(4.2)
(5.1)
63.2 (7.8)
52.2(11.3)
0.93
0.15
0.56
(CG3
each
8.3),
DNA
was
not
CG3
and
CG2.
volume
CG4)
PCR
contain-
and
CG4),
dNTP
0.1
(Pharma-
10 mrvi KC1,
polymerase
and
known
for all patients.
blue
used
CG1
17 index
and
(1 1
green
products
of type
were
I and
to define
representative
type
the CGI
II CG3
of the relative
genes,
17 index,
respectively,
as follows:
(%)
TypeIICG3mRNA
Type
I CG3
mRNA
17 index
ranges
from
-
The
CG1
I C013 genes
type II CG3
was
cancer-related
death
determined
as
Clinical,
histological,
pared
using
the
the
(16),
vival
rates
variate
was
and
was
analysis
used
to MFS
and
the
were
significance
using
the Cox
the independent
the
or
OS
death.
were
x2
the
inter-
and
and
test,
com-
Fisher’s
t test, and Wilcoxon
by the Kapban-Meier
of differences
the
as
parameters
Student’s
estimated
type
only
metastasis
metastasis,
among
U test,
only
in which
diagnosis
biological
appropriate
using
to assess
apparent
1
X
in which
in tissues
between
and
ascertained
mRNA
MFS was determined
detection
of the first
interval
most
II CG3
in tissues
without
exact test, Mann-Whitney
test. Survival
distributions
method
0%,
are transcribed,
to 100%,
genes are transcribed.
Statistical
Methods.
vab between
diagnosis
and
breast
+ Type
log-rank
test
proportional
between
sur( 17). Multi-
hazards
contribution
model
of each
(18)
variable
OS.
(Perkin-
of 30 s at 94#{176}Cand 30 s
previously
PCR
bevels
were
prod-
thermocycler.
PCR prodanalyzed
on a 373A
DNA
se-
resulting
1 19-bp
and
RESULTS
The
DNA
as described
of the
50
of 20 cycles
9600
and
Amplification
and primer
primer
of the
else-
Briefly,
10 jil
of each
polymerase
(primers
in a 20-jil
Tris-HC1
fragment
run consisted
(Perkin-Elmer)
fluorescences
57.7
47.2
the
and 2 jil of the dilution
amplification
(20 cycles)
respectively,
allele-specific
at 65#{176}C
in a Perkin-Elmer
ucts were diluted
50-fold
quencer
described
and CG2),
carried
using
ing 0.1 pmol
(5.0)
(5.3)
-
10 mrvi Tris-HCI
DNA
bp) were diluted
104-fold,
for a second
round of PCR
pmol
as
10 pmol
(primers
ucts (347
were used
cia),
with
of 94#{176}C
for 30 s, 65#{176}C
for 30 s, and 72#{176}C
for 30 s in
amplifications
85.9
90.3
0.024
status
Corp.).
1.5 mrt MgC12,
Amplification
with
100
us-
supplied
assayed
reaction
8.3),
two
99 because
expression
virus
of minor
modifications.
volume
of SO jib containing
transcripts
(Pharmacia),
labeled
100
0
17
12
(10.0)
(9.8)
(9.9)
leukemia
protocol
CG1
dNTP
Elmer).
murine
kit (Perkin-Elmer
each
tial cycles
(8.5)
(8.3)
0.057
(7.7)
(7.6)
37.5
53.3
reverse-transcribed
Core
Assay.
to all CG3
was
Moboney
to the
where
(1 1), with the addition
PCR was carried
out in a final
of the reverse
74.5
52.9
receptor.
of the
The
primer
transcriptase
CG117
(3.7)
(4.6)
0.84
UV irradiation.
GeneAmp
94.6
85.2
estimate.
oligo(dT)l6
reverse
8
22
size
of patients
RT-PCR.
the
0.088
(12.3)
(7.5)
0.33
spectrophotometrically.
ing
P’
(ISyrL
I 5-yr rate
(SE)
0.90
bromide,
under
5-yr rate”
(SE)
0.028
Log-rank
test.
Scarff-Bloom-Richardson
estrogen
receptor;
ethidium
No. of
events
yr)
0.25
eER,
bands
44.6
46.6
node status
a
d
(15
0.27
Node-negative
Node-positive
ER status
+ (10
fmollmg)
(<10
fmol/mg)
PR status
+ (lO
fmol/mg)
(<10
fmol/mg)
Macroscopic
tumor
3O
mm
>30 mm
i.
P’
15-yr rate
(SE)
(6.4)
(5.5)
673
OS
No of
patients”
(%)
Menopausal
status
Premenopausal
Postmenopausal
Histological
graded
I
II
III
Research
OS
MFS
5-yr rate”
(SE)
Cancer
).
The
peak
relaareas
99
was
primary
CG1
17 index
breast
demonstrated
specimens
obtained
cancer
was
determined
patients.
to be negative
after
cosmetic
for tumor
In a previous
in a series
surgery,
mRNAs
study,
of normal
as well
from
this
index
breast
as in a series
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 1998 American Association for Cancer
Research.
674
Prognostic
Value
of CGI3 in Breast
Cancer
100.
6.8%)
(SE
=
81.1%
87.8%
(SE
9.5%)
versus
62.4%
5.7%)
versus
(SE
OS,
I
versus
=
(SE
52.2%
therapeutic
difference
COl
received
37,
25
96.0%
(SE
2.7%);
versus
69.2%
unlikely
the
as frequent
adjuvant
chemotherapy
as it was
15-year
8.6%)].
=
two
To analyze
into
The
with
three
be-
in patients
who
who
hormone
did not ( 16 of
the COb
a positive
equal
17 index
CG1
groups
(16
as a continuous
17 index
(ii
patients
each)
variable,
48)
=
were
with
Using
assessed
the
CG117 negative
index
tumors
of low
and
OS (Table
status
were
Fig. 2 MFS (top) and OS (bottom)
negative COl 17 indexes.
curves
for patients
with
positive
and
index
was
found
CO 1 1 7 index
CO I 1 7 breast
Table
50%.
patients
in 48 (48.5%)
ranged
tumors;
analysis
of the
histopathological
154.2%
[39.6%
with
reduced
17 index.
MFS
for the
significantly
17 index
series
or
of events
showed
risk
that
worse
in
(P
COl
than
terms
that
of
or
a higher
( 16 of
5 1 )] and
(1 1 of 51)]
index
MFS
status
=
a positive
was
0.038;
S 1 patients
[S-year
of
of death
than those
CO]
MFS,
or
size,
receptor
risk
positivity
and OS (P
the
lymph
starelapse
(P
we
but
reduced
MFS
of univariate
17 index.
The
of MFS
a marker
the
analysis
COl
status,
predictive
of node-negative
assessed
]7
of COl
close
had
68.1%
also
patients
(P
a
of
0.04).
=
DISCUSSION
Numerous
immunochemical
and
body
and
response
to
adjuvant
patients
limited
sensitivity
variable
Recent
studies
have
prognostic
marker
its
of
specificity,
(20-22).
on
and
tissues.5
Taken
testis
tissues
together,
a predictor
However,
This
not
demonstrated
results
or CG3
well
due
as
5
Unpublished
are
to the
to
their
used.
that CO
to malignant
analysis,
( 1 1 ), as
these
be
well
a
the
of CO3-
antibodies
restricted
CO
either
as
of
results
may
as
different
studies
was
of
as
tissue
subunit
the frequency
immunohistochemical
presence
prostate
the
both
CG3
immunoassays,
based
production
Using
the
value.
on
the
19).
of both
clinical
most
immunohistochemical
protein
and
(2-9,
in terms
and
based
pointed
therapy
in conflict
positive
COI3
fluids
we
protein
also
and
cells
con-
in normal
as
in normal
breast
advocate
revisiting
CO3
was
=
had
predictive
a negative
(SE
(7
relapsed
was
Fig. 2). The
with
fit
to signif-
associated
17 index
17
few patients
had occurred
who
in the 67 node-positive
that
patients
effect
were
index
the
MFS
progesterone
in identifying
Six of the 7 patients
0.07).
=
COl
firmed
relapse
with a
of recurrence,
positive
sometimes
associwas not
tumor
steroid
17 had
with
of
positive
variable
positivity
menopausal
node
17
0.014)
48 patients
with
99
interest
were
menopausal
not
to the identification
the results
diagnostic
Uni-
were
17
that
postmenopausal
OS,
grade.
status
COl
of both
and
of
Histological
receptor
contribute
samples
above
in the
as macroscopic
lymph
positive
not.
and
positivity
grade
predictive
node
status
showed
predictive
index status on MFS in this subgroup.
Although
into this category
(3 1 cases)
and few events
The
a CO 1 1 7 index
characteristics.
such
COl
of 48
frequency
(x2 test)
positive
mRNAs.
prognostic
99 patients
factors,
grade,
with
COl
outcome
COb
usual
(26 of 48) versus 3 1 .4%
(19 of 48) versus
21.6%
negative
in the
the only classical
explanatory
MFS and OS. COl 17 index
prognostic
Patients
99 tumor
showed
the
the
associated
standard
tus.
4 tumors
to
node status was
ated with reduced
significantly
2 to 95%
I summarizes
according
variate
from
of the
was
lymph
status
1 1 7 index
to
univariate
analysis
were
histological
not shown).
Because
of the major
icance
to breast cancer
in patients
who
tumors
(1 1). A positive
CG1 17
2): high
CO
also
CO 1 17 index
lymph-node
that
(data
relapses),
of normal
breast tissue adjacent
had a positive
index
in their
and
independently
status
at high
Time (years)
status
we
found
after
grade,
and
multivariate
variables
progesterone
might
0
node
This
and
0
histological
not found
were
0.15)
status,
for OS and
MFS.
independent
receptor
p=0.038
for
that
status,
indices.
model,
parameters
(P
receptor
or positive)
lymph
only
of
hazards
significant
menopausal
,
status
positive
I:
value
progesterone
(negative
75
proportional
or nearly
i.e.
status,
Cox
prognostic
be significant
analysis,
the
the
subdivided
intermediate
(13-24%),
and high (25-95%)
outcomes
of the patients
in the three groups
were
to differ.
100.
sig-
populations
(2-12%),
Time (years)
A
for the
and/or
in those
OS,
and
(SE
was
29.6%
[S-year
to account
between
positivity
OS
43.2%).
patients
0
MFS,
and
was
(32 of 62, 5 1 .6%)
15-year
7.8%)]
observed
17 index
postoperative
therapy
:
bias
and
(SE
9.1%)
=
treatment
nificant
cause
4.7%);
=
data.
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 1998 American Association for Cancer
Research.
Clinical
Table
2
Multivariate
analysis
of MFS
and
Regression
coefficient
CGI 17 index status
(positive
vs. negative)
Lymph
node status (positive
vs. negative)
Histological
grade (III vs. II t’s. I)
Menopausal
status (postmenopausal
ts. premenopausal)
PR status
(< 10 t’s.
10 fmol/mg)
a CI,
confidence
interval;
PR,
progesterone
the
fluids
free
from
CO3
diagnostic
patients
with
subunit
value
a variety
in sera
for
from
several
marker.
in various
of tumors.
methods5
nongonadal
of
subjects
translated
in breast
secreted.
ings,
There
including
to detect
that
low
a protein
neoplasms
excreted
that
COf3
mRNA
patients
distinction
was
(3).
normal
breast
acquire
type
tion.
The
COI3
mRNAs
Each type
regardless
classical
was
primary
making
useful
during
is defined
the
CG3
is
factor,
growth
of
RT-PCR
breast
cells
all
enabled
the
Strikingly,
malignant
are
of
from
I genes
II CO3
results
but
could
transformaof type
mRNAs.
The
expressed
as
II
assay
as
and
well
in keeping
with
as
a ratio.
results
molecular
with
a previous
and
lymph
was
node
also
marker
with
report
The
was
the
that
to both
17 index
breast
to early
factor,
cancer
apart
parame-
could
be a
patients.
COb
need
( I .48-18.73)
0.009
0.0 16
0.070
patients.
it has
breast
such
3, and
to bind
cells
(24),
that
recently
to
in term
of CO
suggested
that
the COI3
study
strongly
C013
activity
the free
growth
nerve
platelet-derived
to their receptor
the only
binds
an
because
known
CO
in normal
and
the
heterodimer
with
cluster
and
tion
of these
distinct
CG3
found
that
type
placental
CO3
tumors.
of
stability
gene
identi-
breast
as well
II CG3
the
and
as on
by
C013
transla-
the
specific
products.
(encoded
This
for
was
promoters
of mRNA
transcripts,
I and
transcripts
the
have
(26).
complexity
aggressive
on
the regulation
of the type
(27)
most
focus
of
stimhave
might
apoptosis
level
of CO3
the
will
variants
induce
additional
a subtype
investigations
gene
or smaller
(25) or might
supports
in association
functions
subunit
activity
its
between
whereas
free CO3 has extremely
poor binding
and
capacities
regarding
this receptor.
Several
authors
antiangiogenic
of
and
as
detected
exclusively
in
transformation
similarities
factors,
also
only
relevance
It is noteworthy
receptor),
of type
observed
studies
growth
factor
have the ability
(23).
systemic
the emergence
biological
of a
of such
is in identifying
normally
structural
study
interest
require
phenotypic
growth
transforming
factor 3, which
(CO),
ulating
whether
Crystallographic
other
(LH/CO
main
therefore,
are
CO 1 17-
(6 of 17) of
tumors.
from
population.
reflects
striking
and
as homodimers
fled
simply
with
35.3%
The
who,
which
growth.
showed
patients
with
17-positive
confirmation
particular
or whether
subunit
Oillot
type
et
II CO3
genes)
but not dimeric
CO. COa.
or the 3-core
affected
the
growth
of different
bladder
cancer
cell lines
in vitro.
More
interestingly,
they showed
that the degree
of CO3 stimulation
was
in
index ( 1 1 ). Here,
17 index status of
independent
the COl
group,
related
to be linked
in node-negative
our
1 17
tested.
prognostic
marker
for
and low-risk
patients.
significantly
only
CO
tumors
from
had a positive
that the CO1
status,
suggest
of pri-
relationship
prognosis.
cancer
tissue
is a useful
distinction
between
highpositivity
in a series
its
of the 99 breast
of 30 breast tumors
statistical
evidence
positive
17 index
studied
in 48 (48.5%)
0.009
2.41 (1.23-4.70)
2.81 (1.19-6.63)
2.36 (0.92-6.06)
with
will
transcripts,
cell
Further
as a control
for the other,
to affect
the reliability
of
the CO1
tumors
5.26
as compared
to this
cells,
malignant
detection
as the percentage
serves
known
determined
death
gene
trophoblastic
a!.
positive
and
II CO3
of
of
clearance
allow
type
I and type
because
CO 1 17 index
Our
the
applied
subunits
the importance
approach
also
gene transcript.
expression
1 .66
0.88
1.03
0.86
at high risk of relapse,
therapy.
It remains
to be determined
malignant
enough
molecular
malignant
only
P
0.016
of node-negative
malignancy
find-
that detection
for
to
expressed
risk
2.61 (1.17-5.81)
patients
adjuvant
by a tumor
and
series
a marker,
is thereby
sensitive
bloodstream
RT-PCR
of CO3
type
breast
breast
a clear
relapse
ters.
among
parameters
which 46%
we obtained
from
II gene
we
was
This
The
tissue
human
index
be
and sensitive
and
Relative
0.96
14) of node-negative
larger
are
for these
and
demonstrated
normal
Regression
coefficient
relapsed,
High
assays.
Here,
mary
not
is essential
of CO3 transcript
of most factors
PCR-based
the
specific
(1 1). This
each type
reliable
protein
tumors
receptor
CO 1 17 index
is highly
CO
( 1 of
7. 1 %
node-negative
patients
The latter finding
transcripts
explanations
of secretion
previously
tested
of
that
in serum
into
which
in both
the CO3
may
the level
system,
metabolic
products.
We used a highly
assay
and
that
possible
of the protein
on both
vascular
cells
immunoassays
levels
product
dependent
the
tumor
are several
0.008
0.027
is of
(3), whereas
several
lines of
(this paper)
and immuno-
(2) indicate
2.33 (1.23-4.41)
2.5 1 (1 . 10-5.75)
negative
urinary
levels
of CG3 protein
seem to be an important
prognostic
indicator
in bladder
cancer
(8). However,
it is unclear
why free serum
COI3 is never detected
in patients
with certain
histochemical
P
Only
Detection
nonpregnant
malignancies
such as breast cancer
evidence
using molecular
techniques
risk
CI”)
receptor.
as a diagnostic
or prognostic
immunohistochemical
Other works
document
the presence
of CO3 protein
body
675
OS
Relative
(95%
0.85
0.92
Research
OS
MFS
Variable
Cancer
maximal
have
in the T24
negative
These
genes
and
findings
encode
factors
raise
of variable
status
to assess
was
in human
using
17 index,
a potentially
breast
series
population
of
sensitive,
new
These
findings
of breast
node-negative
cancer
that
tool
type
I and
act as growth
II CO3
receptors.
CO
must
now
and
It will
and simple
gene
for defining
patients
patients.
which
( I 1).
that
specific,
we found
exciting
cancer.
in a larger
that
variants
via unidentified
a highly
12 line,
respectively
the possibility
or smaller
specificity
a COl
in the RTI
CO 1 1 7 indices,
molecules
In conclusion,
test
line and bower
positive
mRNA
prognosis
be confirmed
in a large
be
tempting
Downloaded from clincancerres.aacrjournals.org on June 17, 2017. © 1998 American Association for Cancer
Research.
subto
676
Prognostic
Value
investigate
the
cancers
of
of CG3 in Breast
prognostic
other
Cancer
significance
histological
origin
of the
COb
(prostate,
17 index
bladder,
in
thyroid,
Malignant
colon, uterus,
and so on), in which the expression
of CO3 genes
was demonstrated
to be altered
alongside
malignant
transformation.
Additional
particular
studies
are
contribution
of
also
warranted
these
distinct
to understand
CO3
genes
breast
carcinogenesis.
We thank
Quanta
Medical
and
Michel
Bahuau
the
Center
Ren#{233}Huguenin
for help
and
patient
care.
for assistance
in preparing
staff
for
in performing
this
manuscript.
assistance
the study
We also
in specimen
thank
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