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Molecular Biology and Genetics |
Génome et Cancer UMR 5535 Centre National de la Recherche Scientifique [M. C., F. C., V. J., B. I., H. F., C. T.]; Unité de Biostatistique [A. K.]; Laboratoire de Radio-Analyses [J. G.]; Département d’Oncologie Médicale [S. C.]; Centre de Recherche et de Lutte contre le Cancer Val d’Aurelle-Paul Lamarque, 34298 Montpellier Cedex 5, France
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSConcerted Amplification and...DISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSConcerted Amplification and...DISCUSSIONREFERENCES |
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In a recent study, we analyzed a cohort of 1875 breast tumor DNAs for the amplification status of 26 genes or markers mapping at 15 chromosomal localizations (4) . These genes were selected because they bore functions related to cancer or because they were localized in a chromosomal region known to be frequently amplified. Groups were defined according to correlations observed with classical bioclinical markers as well as associations found among distinct amplification events. Our data showed that it was possible to delineate subgroups of breast tumors according to sets of DNA amplifications. In the present work, we sought to obtain a more complete view of the phenotypic significance of DNA amplifications and therefore investigated their prognostic significance. We therefore studied a cohort of 640 breast cancer patients for whom complete follow-up data could be collected and who corresponded to a subset of the population studied by Courjal et al. (4) . All patients had undergone surgery between 1987 and 1992. DNA amplification events included in this study concerned AIB1 at 20q11, CCND1 and EMS1 at 11q13, ERBB2 at 17q12-q21, FGFR1 at 8p12, MDM2 at 12q13, MYC at 8q24, and RMC20C001 at 20q13. Because the amplification of MDM2 is functionally equivalent to an inactivation of the p53 gene, we searched for p53 mutations by SSCP4 and compared their prognostic significance with that of DNA amplifications.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSConcerted Amplification and...DISCUSSIONREFERENCES |
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In cohort 1, the median follow-up was 66 months (range, 1–121 months). At the time of analysis, 160 patients (25.0%) had relapsed [17 had local recurrence, 21 had contralateral cancer, 11 had nodal metastases, 113 had distant metastases (for 33 of these 113 patients, metastases were at multiple sites), and 5 had developed a second cancer]. Eighty-eight of 160 patients who had relapsed died, 79 from breast cancer.
In cohort 2, the median follow-up was 65 months (range, 1–115 months). At the time of analysis, 141 patients (25.5%) had relapsed [14 had local recurrence, 16 had contralateral cancer, 10 had nodal metastases, 103 had distant metastases (for 29 of these 103 patients, metastases were at multiple sites), and 4 had developed a second cancer]. Seventy-seven of these 141 patients died, 72 from breast cancer.
In cohort 3, the median follow-up was 67 months (range, 1–115 months). At the time of analysis, 118 patients (25.7%) had relapsed [11 had local recurrence, 13 had contralateral cancer, 6 had nodal metastases, 96 had distant metastases (for 23 of these 96 patients, metastases were at multiple sites), and 4 had developed a second cancer]. Sixty-five of these 118 patients who had relapsed died, 61 from breast cancer.
Systemic Adjuvant Therapy.
Following surgery, 24 patients had no additional therapy. Radiotherapy
alone was given to 130 patients, endocrine therapy (tamoxifen) alone to
81, and chemotherapy (generally six courses of 5-fluorouracil,
Adriamycin, and cyclophosphamide) alone to 8 patients. Radiotherapy was
associated with endocrine therapy for 274 patients, with chemotherapy
for 73 patients, and with chemotherapy and endocrine therapy for 45
patients. Chemotherapy was associated with endocrine therapy for five
patients. For 54 patients, the adjuvant treatment was associated with
chemical, radiological, or surgical castration.
Determination of DNA Amplification.
DNA amplification was determined as described previously
(4)
.
Detection of p53 Mutations.
Mutations were searched using the PCR-SSCP method. The analysis was
performed on genomic DNA, and sequences analyzed corresponded to exons
5, 6, 7, and 8. Primers were labeled at their 5' end with a fluorescent
dye, allowing visualization in a ABI-Perkin-Elmer 377 automated
sequencer. Primers were obtained from Genset (Paris, France), and
sequences were as follows: exon 5 forward, 5'-TCTTCCTACAGTACTCCCCT-3',
and reverse, 5'-AGCTGCTCACCATCGCTATC-3' both labeled with HEX; exon 6
forward, 5'-CTGATTCCTCACTGATTGCT-3', and reverse,
5'-CCTCCCAGAGACCCCAGTT-3', labeled with TAMRA; exon 7 forward,
5'-TTATCTCCTAGGTTGGCTCT-3', and reverse 5'-GCTCCTGACCTGGAGTCTTC-3',
labeled with FAM; exon 8 forward, 5'-CTTCTCTTTTCCTATCCTGAG-3', and
reverse 5'-CCTCCACCGCTTCTTGTCCT-3', labeled with TET. These primer sets
defined PCR products of 205, 168, 136, and 191 bp, respectively. PCR
reactions were run in separate tubes, and PCR products were pooled for
SSCP analysis. The loading mixture was prepared by the addition of 0.7
µl of the PCR mixture to 2 µl of sequencing loading dye (95%
formamide and dextran blue). This mixture was heat-denatured at 95°C
for 3 min and chilled on ice. The denatured sample was subsequently run
on a MDE (Bioprobe System-TEBU, Le Perray en Yvelines, France)
gel containing 2% glycerol in 1x Tris-borate EDTA. The gel was then
run at 6W constant power for 4 h at 20°C. The electrophoretogram
was then analyzed using the Genescan 2.0 program. Samples displaying
abnormal bandshifts were reamplified and reanalyzed for confirmation
using the same method.
Statistical Analysis.
Statistics were calculated using Statview software (Abacus Concepts,
Berkeley, CA). Statistical correlations between different gene
alterations and between clinicopathological parameters and alterations
were determined by the 
2 test. DFS was defined
as the time from surgery to the first local or distant recurrence or to
last contact. Contralateral tumor and second cancer were not considered
as recurrences for DFS determination. Breast cancer-specific OVS was
defined as the time from surgery to death if the patient died from
breast cancer or to last contact. Five-year survival rates were
estimated, and survival curves were plotted according to Kaplan and
Meier (5)
. Differences between groups were calculated by
the log-rank test (6)
. In multivariate analysis, relative
risk of recurrence or death from breast cancer, 95% confidence
intervals, and P values for censored survival data were
calculated by use of Cox’s proportional hazards regression model
(7)
. All P calculations were two-sided and
P was considered significant at <0.05. Different Cox models
were built in which only clinical parameters bearing prognostic
significance were included. Cox model I (cohort 3) included nodal
status, clinical tumor size, SBR grade, and ER status; Cox model
II (node-negative patients selected from cohort 2) included clinical
tumor size and ER status; Cox model III (node-positive patients
selected from cohort 2) included PR status. Clinical parameters were
dichotomized as follows: nodal status (
1 versus no
positive lymph node), clinical tumor size
(T3-T4 versus
T1-T2), SBR tumor grade
(1–2 versus 3), ER [low (
10 fmol/mg protein)
versus high (>10 fmol/mg protein)], PR [low (10 fmol/mg
protein) versus high (>10 fmol/mg protein)]. A stepwise
regression analysis was performed that included nodal status, clinical
tumor size, SBR grade, ER status, PR status, and the molecular
parameters that were significant at the 0.1 level in the univariate
analysis. For each molecular parameter, patients with missing
information were considered as a separate category and included in the
analysis as well. In each case, we verified whether the category
"missing information" was associated with a significant prognostic
value.
Data Management.
The data were organized in a computer-assisted database run under
Paradox 7.0 (Borland, Scotts Valley, CA). A file containing the
data presented here has been deposited on our ftp server at the
following address: ftp.igm.cnrs-mop.fr; login, "anonymous;"
password, email address of the person calling in; pathway,
"anonymous/cuny99." This file is under the dbase IV format and is
named "mccrdata.dbf." An Excel file presenting the organization,
named "mccrdata.xls," can be found in the same subdirectory.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSConcerted Amplification and...DISCUSSIONREFERENCES |
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Table 1
presents the clinicopathological characterization. The distribution of
bioclinical markers was in good agreement with previously reported
data, indicating that our cohort was representative of breast cancer
patients. DFS and breast cancer-specific OVS rates were estimated and
compared by univariate analysis on these characteristics. Statistically
significant associations were observed for clinical tumor size, nodal
involvement, tumor grading, and ER status with both DFS and OVS. PR
status correlated only with OVS. No significant differences were
observed for age and histological type.
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. These genes or loci were chosen on the basis of three criteria, two
of which had to be met: amplification in at least 5% of the analyzed
tumors; existence of positive correlations with clinicopathological
parameters; or proven oncogenic properties. CCND1
amplification correlated with ER and PR positivity, nodal involvement,
and invasive lobular carcinoma; EMS1 amplification
correlated with ER and PR; ERBB2 with loss of ER and PR and
carcinoma of the ductal type; and MYC with loss of ER and
PR. Trends of association were observed for AIB1 and
FGFR1 with the presence of ER. Correlations between
amplifications occurring at nonsyntenic loci were also found. As
described previously, strong correlations were observed between
amplifications of CCND1 and/or EMS1 (11q13) and
FGFR1 (8p12), MYC (8q24) and ERBB2
(17q21), as well as MDM2 (12q13) and AIB1 (20q11)
(4
, 8)
. In addition, we searched for p53
mutations at the genomic DNA level using fluorescent PCR-SSCP. We
screened exons 5, 6, 7, and 8, and overall, 14.1% of tumors presented
variant migrating bands when analyzed by SSCP in either exon (Table 2)
.
The occurrence of p53 mutations (identified solely on the
basis of SSCP) correlated with loss of ER and PR, as well as high-grade
tumors. Noticeably, no positive correlation was observed between
p53 mutations and amplification of any of the tested loci.
On the contrary, an exclusion was observed between p53
mutations and MDM2 amplification.
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Amplification of CCND1, EMS1, and
FGFR1 correlated with reduced DFS and OVS, whereas
p53 mutations (for exons 5 and 7; no correlation was
observed when all exons were considered) correlated with reduced OVS
only. Amplification of MDM2 presented a trend of association
with DFS, and that of the RMC20C001 locus presented a trend
with both reduced DFS and OVS. MYC, ERBB2, and
AIB1 could not be related to a worsened course of the
disease. Because nodal status bears strong prognostic significance and
is a key parameter in clinical management, we searched for correlations
in the node-negative (N-) and node-positive
(N+) subgroups of patients. In
N- patients, MDM2 amplification and
p53 mutations correlated with reduced DFS and OVS, whereas
amplification of FGFR1, CCND1, and
EMS1 correlated with DFS and OVS in the
N+ group. In this latter group, we also noted a
weak correlation of ERBB2 amplification with OVS (data not
shown).
Multivariate Analyses.
Multivariate analyses were undertaken on cohorts 2 and 3 to evaluate
the risk of relapse and death related to each of the nine molecular
markers tested here. Each marker was adjusted based on nodal status,
clinical tumor size, ER and PR status, and tumor grade. Different Cox
models were used according to the population of patients tested,
including the clinical parameters that remained significant. Cox model
I was used for cohort 3, whereas Cox models II and III were used for
the N- and N+ subgroups of
patients selected from cohort 2. The relative hazard rates of
recurrence and death from breast cancer are shown in Fig. 1
for the significant parameters only. Amplification of EMS1,
FGFR1, MDM2, and RMC20C001 were retained in
Cox model I for DFS, whereas only CCND1 and
RMC20C001 were significantly associated with reduced OVS
(Fig. 1)
. Interestingly the amplification of RMC20C001,
which showed borderline significance in the univariate test, correlated
with both reduced DFS and OVS in the multivariate analysis. When
stratified according to nodal status, MDM2 and
p53 mutations (selecting mutations in exons 5 and 7) showed
an association with reduced DFS and OVS in N-
patients. Similarly, CCND1, EMS1, and
FGFR1 correlated with reduced DFS and OVS in the
N+ group (Fig. 1)
.
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, tumor size, nodal status, tumor grade, and amplification of
RMC20C001, MDM2, and EMS1 were the
major independent prognostic indicators for DFS. When the selected
molecular parameters were ranked according to P, the
following relative order was observed: RMC20C001 > MDM2 > EMS1. Parameters
selected for OVS were very similar except that PR was selected and
EMS1 was replaced by CCND1; their relative rank
was RMC20C001 > MDM2 > CCND1. In N- patients, tumor
size, ER, MDM2 amplification, and p53 mutations
were selected as independent prognostic indicators for both DFS and
OVS. In N+ patients, EMS1
amplification was the only molecular parameter selected together with
SBR grade for DFS and with PR for OVS (data not shown).
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Concerted Amplification and Clinical Outcome |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSConcerted Amplification and...DISCUSSIONREFERENCES |
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(DFS) and Fig. 2B
(OVS), patients with
tumors presenting no amplification at any of the tested loci did not
show a significant difference in survival time compared with those with
only one amplified locus. Interestingly, a significant difference was
seen when patients showing two or more amplified loci were compared.
This was true for DFS as well as OVS. We next tested a cooperative
effect for strongly correlating coamplifications. We analyzed the
survival rates of patients showing either concomitant amplifications of
CCND1 and FGFR1 or coamplification of
ERBB2 and MYC to determine whether these fared
worse than those with only one of these genes amplified.
Coamplifications of CCND1 and FGFR1 as well as of
ERBB2 and MYC were associated with significantly
lower survival rates. The increased risk associated with the
CCND1-FGFR1 coamplification could be evidenced
both at the DFS and OVS levels and was strongest in the
N+ subgroup of patients (data not shown).
Interestingly, the survival time of patients with either
CCND1 or FGFR1 amplified was intermediate to that
of patients presenting the coamplification (Fig. 2C)
. This
contrasted with the ERBB2 and MYC situation.
Noticeably, patients bearing either ERBB2 or MYC
amplified did not present an increased risk compared with patients
showing neither of the two. Only when both genes were coamplified was
reduced DFS or OVS demonstrated (Fig. 2D)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSConcerted Amplification and...DISCUSSIONREFERENCES |
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Of the nine parameters studied, six (FGFR1, CCND1, EMS1, RMC20C001, MDM2, and p53 mutations) correlated with bad prognosis in either the univariate or multivariate analysis on the whole population of patients. Using a stepwise analysis, we could show that RMC20C001, MDM2, and EMS1 were independent prognostic indicators for DFS; interestingly for OVS, EMS1 was replaced by CCND1. Because nodal invasion is a determining factor in clinical management of breast cancer, the prognostic significance of these genetic anomalies was also studied in node-negative and node-positive subgroups of patients. It was noticeable that amplification of MDM2 and mutations of p53 correlated with reduced DFS and OVS in the N- group. Amplification of CCND1, EMS1, and FGFR1 correlated with reduced DFS and OVS in the N+ group.
This is the first time to our knowledge that amplifications of AIB1, FGFR1, and MDM2 have been studied in terms of prognostic significance in breast cancer. Despite its correlation with ER+ breast tumors (8) , our data do not associate AIB1 amplification with a worsened course of the disease. Our results for FGFR1 amplification are consistent with recent data by Blanckaert et al. (9) , who described an association between increased binding activity of basic fibroblast growth factor receptors and reduced DFS and OVS in breast cancer patients. Similarly, the overexpression of p95/MDM2 in breast cancer has been correlated with poor prognosis in an unselected set of patients (10) . Our data thus are in keeping with these observations with the exception that in that study (10) , 46% of the breast tumors analyzed were scored positive, which is almost 10-fold higher than our rate of MDM2 gene amplification. MDM2 gene amplification and p53 mutations were the only abnormalities bearing prognostic significance in N- patients, suggesting that both anomalies could have similar phenotypic consequences in breast cancer. This can be related to the role of the MDM2 protein, which is known to act as a negative regulator of the p53 protein by routing it toward active degradation (11) . Our results are in concordance with most studies performed at the molecular level on p53 mutations in breast cancer, which have shown a correlation with poor outcome (12, 13, 14, 15, 16, 17, 18, 19, 20, 21) . Interestingly, in our set of patients, the prognostic significance of p53 was restricted to mutations in exons 5 and 7 (22) . The difference in prognostic significance according to which codon or exon is mutated remains disputed; however, our data are in concordance with an analysis suggesting that mutations affecting two regions encompassing codons 163–195 (corresponding to conserved region III and part of exon 5) and codons 236–251 (conserved region IV and exon 7) are associated to a worse prognosis (18 , 23) .
Other parameters analyzed here have all been studied at variable
extents in terms of their prognostic significance, and our data are
globally in agreement with published results. Some small differences
could be seen however; Tanner et al. (24)
reported that amplification of RMC20C001 correlated with
reduced DFS in node-negative patients, whereas our data showed evidence
of a correlation with bad prognosis in the total population. It is of
note that RMC20C001 is an anonymous probe subcloned from a cosmid and
that two recently identified genes map in its vicinity; the
transcription factor ZNF217 (25)
and the serine
threonine kinase STK15 (26)
. Both genes have
been found amplified and overexpressed in 5–10% of breast tumors. We
noted that ERBB2 amplification showed only a weak
correlation with reduced OVS in univariate analysis in
N+ patients (data not shown). This does not
strongly support the prognostic value of ERBB2 in breast
cancer, and this issue has been debated, leading to the proposition
that this could be related to the fact that ERBB2
amplification is not an independent factor (27)
. Some
reports have indicated that CCND1 amplification (or that of
nearby mapping genes INT2/HST) has prognostic
value in unselected populations (28
, 29)
. In our study,
CCND1 and EMS1 were closely associated in terms
of prognostic significance, and both correlated with worsened outcome
in the N+ group of patients. This is in keeping
with the literature, which show a prognostic significance of
CCND1 in N+ patients (28
, 30
, 31) . However, our results are more contrasted for
EMS1, because Hui et al. (31)
reported a correlation with a worsened course of the disease in
N- patients while finding a correlation for
CCND1 in the N+ group. This
dissociation between CCND1 and EMS1 is in
contrast with our data, which show that 87% of the tumors amplified
for EMS1 show CCND1 amplification as well. This
is explained by the fact that both genes map 
1.5 Mb from each other
on chromosome 11q13 (32)
. In line with this, we observed
in the stepwise analysis that both variables were colinear. Moreover,
we observed that inclusion of FGFR1 in the stepwise analysis
excluded both CCND1 and EMS1 and that the reverse
was also true, thus indicating that these three markers were linked.
This can be related to the frequent coamplification of
CCND1-EMS1 with FGFR1 (40% of the
tumors amplified for FGFR1 are coamplified for
CCND1; Ref. 4
). This coamplification can lead
to the formation of a hybrid amplification unit (33)
.
Cooperative Effect of Concomitant Amplifications.
It has long been known that the more advanced a cancer is, the more
rearranged the genome is (34)
. We were, therefore,
interested in verifying whether there was an association between the
number of genetic alterations observed in a tumor and a worsened
outcome of the disease. Our analysis of patient survival according to
the number of amplified loci revealed that patients whose tumors
presented two or more amplified loci had a significantly reduced
survival compared with patients showing only one or none at all. We
investigated whether this was due solely to the number of amplified
loci or whether the type of genes involved made a difference. To
address this question, we selected pairs of frequently coamplified
markers and studied their relation to disease outcome. The
amplifications of CCND1 and FGFR1 as well as
ERBB2 and MYC presented a strong correlation in
breast tumors, and this could indicate the existence of a selective
advantage associated with their coamplification. This hypothesis is
supported by our findings showing that concomitant amplification of
either CCND1 and FGFR1 or ERBB2 and
MYC is associated with a significant reduction of the
patient’s survival. It is of note that this cooperative effect was not
observed when alternative pairs, such as CCND1 + x (x being any gene other than FGFR1
or EMS1) or ERBB2 + x
(x excluding MYC) were tested. This could suggest
a cooperative effect. It may also be of interest that neither
ERBB2 nor MYC were associated with a worsened
course of the disease when tested on their own in our data set.
Genotyping Breast Tumors to Delineate Phenotypic Subsets.
Over the past few years, a considerable effort has been made to
characterize genetic abnormalities in cancer, the general idea being
that tumor genotyping would be valuable in defining cancer phenotypes.
In a previous study, we showed that it was possible to delineate
subsets of breast tumors according to specific combinations of DNA
amplifications (4)
. The present work allowed us to extend
the phenotypic description to prognostic significance. We show here
that some of the markers tested presented prognostic significance in
specific subsets of patients. This was particularly evident for
MDM2 amplification and p53 mutations, which
showed a strong prognostic value in the N-
subset of patients, or for the amplification of CCND1,
EMS1, and FGFR1 in N+
patients. During the course of this study, we also made some
observations that suggest the existence of correlations clustering in
other patients subsets, such as MYC in patients under 50
years or MDM2 in ER+ patients (data
not shown). Our data constitute an attempt to delineate tumor subsets
according to their genotypic specificity. Knowing the complexity of the
genetic rearrangements in breast cancer, the nine events studied here
probably correspond to a small portion of the genes involved in
tumorigenesis. Genotyping of breast tumors will involve the analysis of
an ever larger number of parameters and sorting of the significance of
complex combinations. Because different combinations of genes or
genetic anomalies may bear a meaning in different populations of
patients, the analysis of specific phenotypic subsets will be
necessary, thus leading to an increase of the number of comparisons.
This will require the analysis of very large cohorts of patients
(several thousand) and consequently the use of high-throughput
analytical methods (35)
in association with statistical
tools especially devised for multiple-comparison analyses.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by funds from the Ligue Contre le
Cancer, Fédération des Entreprises en Lutte contre le
Cancer. 
2 Permanent address: Department of Surgery,
University of Western Australia, Nedlands, 6907 Australia.
3 To whom requests for reprints should be
addressed, at Génome et Cancer UMR 5535 CNRS, Centre de
Recherche, CRLC Val d’Aurelle-Paul Lamarque, 34298 Montpellier Cedex
5, France. Phone: 33 (0)467 613 766; Fax: 33 (0)467 613 041; E-mail: theillet{at}valdorel.fnclcc.fr
4 The abbreviations used are: SSCP, single-strand
conformational polymorphism; ER, estrogen receptor; PR, progesterone
receptor; DFS, disease-free survival; OVS, overall survival; SBR,
Scarff, Blum, and Richardson.
5 Several of the patients belong to more than one
group.
Received 5/ 7/99. Accepted 12/15/99.
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W. Han, D. Kang, I. A. Park, S. W. Kim, J. Y. Bae, K.-W. Chung, and D.-Y. Noh Associations between Breast Cancer Susceptibility Gene Polymorphisms and Clinicopathological Features Clin. Cancer Res., January 1, 2004; 10(1): 124 - 130. [Abstract] [Full Text] [PDF]
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A. Myoui, R. Nishimura, P. J. Williams, T. Hiraga, D. Tamura, T. Michigami, G. R. Mundy, and T. Yoneda C-Src Tyrosine Kinase Activity Is Associated with Tumor Colonization in Bone and Lung in an Animal Model of Human Breast Cancer Metastasis Cancer Res., August 15, 2003; 63(16): 5028 - 5033. [Abstract] [Full Text] [PDF]
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E. L. Goode, A. M. Dunning, B. Kuschel, C. S. Healey, N. E. Day, B. A. J. Ponder, D. F. Easton, and P. P. D. Pharoah Effect of Germ-Line Genetic Variation on Breast Cancer Survival in a Population-based Study Cancer Res., June 1, 2002; 62(11): 3052 - 3057. [Abstract] [Full Text] [PDF]
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H. Wang, L. Nan, D. Yu, S. Agrawal, and R. Zhang Antisense Anti-MDM2 Oligonucleotides As a Novel Therapeutic Approach to Human Breast Cancer: In Vitro and in Vivo Activities and Mechanisms Clin. Cancer Res., November 1, 2001; 7(11): 3613 - 3624. [Abstract] [Full Text] [PDF]
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