Download BRCA2 and p53 Mutations in Primary Breast

(CANCER RESEARCH 58. 859-862.
March 1. 19981
Advances in Brief
BRCA2 and p53 Mutations in Primary Breast Cancer in Relation to
Genetic Instability1
Solveig Gretarsdottir, Steinunn Thorlacius, Rut Valgardsdottir, Sigfridur Gudlaugsdottir, Stefan Sigurdsson,
Margret Steinarsdottir, Jon Gunnlaugur Jonasson, Kesara Anamthawat-Jonsson, and Jorunn E. Eyfjörd2
Molecular
and Cell Biology Research Laboratory.
Icelandic Cancer Society ¡S.Gr., S. T.. R. V.. S. Gu., S. S.. J. E. £./.•
Cylogenetics
Laboratory
¡M.S.] and Department
of
Pathology IM. S.. J. G. J.]. University Hospital of Iceland; and Biology Department. University of Iceland IK. A. J.j. Reykjavik. Iceland
population.'
Abstract
This enabled us to analyze over 400 consecutive breast
cancer cases for somatic p53 mutations, as well as for the germ-line
BRCA2 founder mutation. A subset of samples were studied by
conventional cytogenetic methods. FISH,4 and flow cytometry. thus
The products of the BRCA breast cancer susceptibility genes have been
implicated in cell cycle control and DNA repair. It has been suggested that
mutations in the p53 gene are a necessary step in tumorigenesis in BRCA
tumors. We tested samples from 402 breast cancer patients for germ-line
allowing analysis of genetic instability in relation to these two genes.
BRCA2 and p53 mutations in tumors. p53 mutations are more frequent in
BRCA2 mutation carriers than they are in controls. Tumors with muta
tions in either gene had multiple chromosomal abnormalities, as shown by
cytogenetic analysis.
Materialsand Methods
The study material consisted of 402 breast tumor samples from the Icelandic
Cancer Society Tumor Specimen Bank.
Samples were screened for mutations in exons 5-8 of the p53 gene with the
Introduction
constant dénaturantgel electrophoresis method (19). p53 mutation status in
relation to prognosis has been previously published for the majority of these
samples (20-22). BRCA2 exon 9 fragments were PCR-amplified and run on
Germ-line mutations in the BRCA I and BRCA2 genes have been
shown to predispose to breast cancer (1-3), and the most common
somatic changes found in breast tumors are mutations in the p53 gene
(4). Both the BRCA and p53 genes have been implicated in cell cycle
control (5-7). A number of studies have shown that p53 mutations are
associated with genomic instability in tumors (8, 9), and recent studies
on the functions of the BRCA proteins suggest that they are also
involved in control of genomic integrity (10, 11). Both BRCA pro
teins and p53 have been shown to interact with hRad51, a human
homologue of the yeast Rad51 protein that is involved in recombina
tion and DNA double-strand repair (10-12). BRCA1 and BRCA2
deficiencies cause cell lethality in early mouse embryos (13, 14), and
hypersensitivity to -y-irradiation is seen in BRCA2 —¿/-cells (11).
Recent studies show that BRCA1- and BRCA2-deficient embryos can
6% denaturing polyacrylamide gels for mutation detection (17). Mutants were
identified by the presence of an extra alÃ-ele.
Tumors were harvested directly for cytogenetic analyses or cultured on
average for 6-7 days before harvesting (23). Analysis of karyotypes was done
according to an International System for Human Cytogenetic Nomenclature
(24). Karyotypic clones with one to three numerical changes (i.e.. additional or
lacking chromosome) or a single structural change (i.e.. translocation or
deletion) were listed as having simple clonal changes. Clones with more than
three numerical changes and/or more than two structural changes were called
complex.
FISH was performed using PCR-amplified whole chromosome probes for
chromosomes 1, 3, 16, and 17, as described by Anamthawat-Jonsson
et al.
(25), in which chromosomes 1 and 3 were labeled with red rhodamine and
chromosomes 16 and 17 were labeled with green fluorescein.
Flow cytometry was used to analyze the DNA content of the tumor cells.
DNA ploidy index and S-phase assessment were performed as described
previously (26). Histograms were classified as diploid (DNA index = 1), if
there was a single G,/G, peak, or aneuploid (DNA index ^ 1), if there were
at least two clearly distinct peaks, including multiploid, if more than two peaks
were seen. The median S-phase value of <7% was defined as low S-phase
fraction, and £7% was defined as high S-phase fraction.
For statistical analysis, the jf test and Fisher's exact test were used as
be partially rescued by p53 or p21 null mutations (13, 14). This
suggests that cells with nonfunctional BRCA can only survive if they
also have defective checkpoint control. Germ-line mutations in
BRCA 1 or BRC A2 increase the risk of breast cancer, but even in these
hereditary cases, breast cancer is a multistep process, and somatic
mutations in other genes play a part in the tumor formation. Recent
publications suggest that p53 abnormalities are a necessary step in
tumorigenesis in BRCA1 carriers (15, 16). We wanted to examine this
in an unselected group of breast cancer patients and test whether
BRCA2 abnormalities were associated with genomic instability in
tumors.
Family and population studies indicate that there is only one mu
tation in each BRCA gene in the Icelandic population, one rare
BRCA1 mutation (D1692N) and a common BRCA2 founder mutation
(999del5), found in 8% of all breast cancer cases in Iceland (17, 18).
There are no indications of other BRCA 1 or BRCA2 mutations in the
appropriate.
The germ-line mutation screening was approved by the Icelandic Cancer
Society Institutional Review Board. All DNA analyses were performed
samples without personal identification.
on
Results
p53 and BRCA2 Mutation Analysis. Samples from unselected
breast cancer patients (n = 402) were screened for BRCA2 and p53
mutations. The BRCA2 999del5 germ-line mutation was detected in
samples from 34 patients (8.4%), and somatic mutations in the p53
gene were detected in 72 (17.9%) tumors. The p53 mutations were
distributed as follows: 25 mutations in exon 5 (35%), 9 in exon 6
(12%), 17 in exon 7 (24%), and 21 in exon 8 (29%).
We compared the frequency and pattern of p53 mutations in tumors
Received 11/4/97; accepted 1/19/98.
The cosls of publication of this article were defrayed in part by the 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.
' This work was supported by grants from The Icelandic Cancer Society Fund. Nordic
Cancer Union. Icelandic Research Fund for Higher Education. University of Iceland
Science Fund, and Icelandic Science Council.
2 To whom requests for reprints should be addressed, at Molecular and Cell Biology
1 Unpublished results.
4 The abbreviation used is: FISH, fluorescence in situ hybridization.
Research Laboratory, Icelandic Cancer Society, P.O. Box 5420. 125 Reykjavik. Iceland.
E-mail: [email protected].
859
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BRCA2 AND p53 MUTATIONS
IN PRIMARY
Table I Frequency- of p53 mutations in tumors from BKCA2 mutation carriers and
noncarriersa
p53wl
BRCA2wt (n = 368)
BRCA2mul (n = 34)
306
24
mulated
(76.5%) and compared to the controls. There was, however, a clear
difference observed in the complexity of the clonal changes. All of the
clonal changes detected in the BRCA2 and p53 mutated tumors were
complex as compared to about half of the clones in the mutant-
p53mut
62
10
BRCA2wt.
BREAST CARCINOMAS
0.09
BRCA2;
negative tumors (Table 3). The chromosomal aberrations included
both structural and numerical changes, they were not restricted to any
particular chromosome and polyploidy was highly prevalent. How
ever, among the primary breast tumor samples, chromosomes 1, 3, 16,
Table 2 p5J mutations found in tumors from BRCA2 carriers
and 17 were most frequently abnormal and were, therefore, selected
Sample123456789IOExon5555677888Codon182173174141ND">NDNDNDfc298-302NDMutation1-base
for FISH analysis with whole chromosome paint. The FISH analysis
deletionGTG->ATGCAT—CTTTGC—
confirmed the structural instability detected by G-banding and, fur
thermore, showed that chromosomal rearrangements, gains, and losses
CGCLarge
were common. Multiple rearrangements of the painted chromosomes
were detected in samples with BRCA2 germ-line mutations, p53
"p53wt,
wild-type
p53; p53mut.
p53;
wild-type
BRCA2mul, mutated BRCA2.
deletionLarge
deletion14-bp
somatic mutations, and both BRCA2 and p53 mutations (Fig. l, B, D,
and F). Tumors with both BRCA2 and p53 mutations were not more
complex than tumors with either mutation alone.
S Phase. The proliferation rate of the tumors was examined. Both
BRCA2 and p53 mutations were associated with a very high prolif-
deletion
" ND. not determined.
* Samples from paraffin-embedded
material. Mutation was not verified by sequencing.
The mutations in samples 5, 8, and 10 were clearly detectable with the constant dénaturant
gel electrophoresis method, which was used for the p53 mutation screening. This is a
highly sensitive method that has enabled us to detect mutations in tissue with as little as
25% tumor cells.
erative rate, with approximately 70% of tumors showing high mitotic
activity, indicated by a high S-phase fraction (S7.00). This associa
from BRCA2 carriers and noncarriers. We found that 10 BRCA2
mutation carriers (29%) had p53 mutations in their tumors or nearly
twice as many as in the BRCA2 wild-type group (17%; Table 1). This
Discussion
Here, we screened samples from 402 unselected breast cancer
patients for BRCA2 germ-line mutation and p53 mutations in primary
difference was, however, not significant. The p53 mutation distribu
tion in the BRCA2-positive group was similar to that found in the
whole group (Table 2).
Flow Cytometry, Cytogenetic,
and FISH Analyses.
tion was significant in all groups (Table 3).
tumor samples. The frequency of BRCA2 mutation carriers (8.4%)
was in agreement with our previous studies on Icelandic breast cancer
patients (18). We detected mutations in exons 5-8 of the ¡>53
gene in
Flow cyto-
17.9% of the tumors. This was also in agreement with our previous
findings (20-22) and those of others (4, 27).
metric analysis of DNA content was performed on 266 of the samples
(Table 3). Aneuploidy was detected in 65% of all samples, and the
prevalence was similar to that in BRCA2 mutants and wild-type
samples. The same was true for the p53 mutated samples. Cytogenetic
analysis was performed on fresh tumor samples from 60 patients
(Table 3). There was no significant difference between samples from
tumors with BRCA2 mutation compared to wild type, based on the
occurrence of simple and/or complex clonal changes. The Cytogenetic
and flow cytometry data combined showed that 73% of the samples
from BRCA2 carriers were aneuploid, compared to 63% of the
BRCA2/p53 normal samples. The instability trend was further
strengthened if BRCA2 and p53 mutated samples were pooled
p53 mutations were found to be more common in tumors from BRCA2
mutation carriers than they were in controls. However, the frequency was
not as high as those recently reported in breast tumors from BRCA1
mutation carriers (15). In that study, p53 mutations were found in eight of
eight tumors with known BRCA1 mutations, and the majority of p53
mutations were located in exon 5. The distribution of p53 mutations
found in our study was the same in BRCA2 mutation carriers as in the
whole group. None of the mutations reported in the BRCA1 carriers by
Crook et al. (15) were found. p53 protein overexpression in BRCA1
tumors from high-risk families also indicate a fairly high frequency of
Table 3 Association of BRCA2 and/or p53 mutated samples with flow cytometry and Cytogenetic data
The mutated samples were compared to the wild type using the Fisher's exact test. Abbreviations are as in Table 1.
BRCA2mutPloidy
P450.5
p53mul
p53mut6217(27.5)45
or
BRCA2wl/p53wt2040.17
266)TotalDiploid
(n =
(%)Aneuploid
(%)S-phase
255)Total<7.00(%)27.00
(n =
(78)420.04
0.0635
10(22)
(%)Cytogenetics
60)TotalNo (n =
(69)110.7
<%)Clonal
clonal changes
(%)Clonal changes
32)TotalSimple
changes (n =
0.57(64)70.12
(%)Complex
(%)Ploidy
217)TotalNormal
and cytogenetics (n =
0.067(100)470.390
77(38)127(62)1980.0009
(72.5)5717(30)40
0.00629
13(31)
109(55)89
(70)177(41)10(59)10010(100)6415(23)49
(45)430.8
4 (36)
(49)22(51)220.013
21
10(45)12
(55)2130.05
(%)Abnormal
0.01738
9(20)
(%)268(31)18(69)227(32)15(68)83(37)5(63)505(100)267(27)19(73)P(80)BRCA2mut
(37)134(63)
79
(77)P
860
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BRCA2 AND p53 MUTATIONS
IN PRIMARY
BREAST CARCINOMAS
i
*tt
•¿â€¢J
Fig. 1. FISH with whole chromosome painting showing structural abnormalities in metaphases (ß.O, and F). The cells were counterslained with 4'.6-diamidino-2-phenylindo!e
(A,
C. and £7).
&•«/('
bar. K) ¿im.The chromosome abnormalities involved both structural and numerical changes, and they are of very complex type, based on G-handing and FISH analysis.
A and R, near-triploid cell from a tumor from a BRCA2 mutant carrier after painting of chromosomes I and 16 (red and gMtii/btOtttetOCtt
respectively). Chromosome I is involved
in eight translocations and shows overall gain of material, but chromosome 16 is seen in one translocatton and shows loss of material. C and D, near-triploid cell from p53 mutated
tumor after painting of chromosomes 1 and 16 (red and green fluorescence, respectively). Here, chromosome 1 lakes part in two trän
s locations, and chromosome 16 shows gain. E
and F. near-diploid cell from a BRCA2 and p53 mutated tumor after painting of chromosomes 3 and 17 (red and green fluorescence, respectively). In this cell, four rearrangements
can be seen, one of which is a translocation between the two painted chromosomes.
861
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BRCA2 AND p53 MUTATIONS
[N PRIMARY
BREAST CARCINOMAS
mutations
p53 abnormalities, 40 and 70%, respectively (16,27). p53 overexpression
was not associated with BRCA2 mutation in our study (data not shown).
The samples analyzed in this study were from breast cancer patients
unselected for family history. Ten of the BRCA2 mutation carriers were,
however, found to belong to known high-risk families (17). Of those,
in human tumors and cell lines. Nucleic Acids Res.. 22: 3551-3555,
1994.
Vaughn, J. P., Cirisano, F. D., Huper. G., Berchuck, A., Futreal, P. A., Marks, J. R.,
and Iglehart, J. D. Cell cycle control of BRCA2. Cancer Res., 56: 4590-4594, 1996.
Rajan, J. V., Marquis, S. T., Gardner, H. P.. Chodosh, L. A., Rajan, J. V., Wang, M.,
Marquis. S. T.. and Chodosh, L. A. Developmental expression of Brca2 colocalizes
with Brea I and is associated with proliferation and differentiation in multiple tissues.
Dev. Biol.. 184: 385-401, 1997.
Levine. A. J. p53, the cellular gatekeeper for growth and division. Cell, 88: 323-331,
only three had p53 mutations, and there was one additional case of p53
overexpression. Soboi et al. (16) suggest that specific mutations in the
BRCAI gene are more often associated with p53 abnormalities as meas
ured by abnormal staining. Because all of the BRCA2 mutation carriers
in our study have the same 999del5 mutation, no conclusion can be drawn
about association between p53 abnormalities and BRCA2 mutations in
general. As mentioned previously, only one rare BRCAI mutation has
been found in this population. A single case of this mutation was found
in this cohort. Neither p53 mutation nor abnormal p53 staining was
detected in a tumor sample from this patient.
We previously described a significant association between p53 abnor
malities and genomic instability in primary breast tumors (9, 22). This
study supports this and, furthermore, shows that BRCA2 mutated tumors
have complex chromosomal changes as well. Culturing primary breast
tumor cells is difficult, and in particular, it is hard to get cells with
complex karyotypes to divide. The most abnormal cancer cells may,
therefore, be lost in the process of cell culture and chromosome harvest
ing. The BRCA2 samples were, indeed, highly complex showing multi
ple chromosomal rearrangements (e.g.. Fig. Iß),which seems to fit the
notion of BRCA2 involvement in double-strand DNA repair.
It is well known that p53 participates in cell cycle control by activating
p21 in response to DNA damage (29). It has been shown that the
expression of the BRCA genes is cell cycle dependent (5, 30), and in a
recent study, BRCAI was found to activate p21 in a p53-independent
manner (31 ). It is as yet unknown how BRCA2 participates in cell cycle
control. We found that tumors from BRCA2 mutation carriers were
highly proliferative, as judged by high S phase. This was also true for
tumors without additional p53 abnormalities, suggesting a possible role
for BRCA2 in cell cycle control.
In conclusion, our results support findings that implicate BRCA2 in
DNA repair and cell cycle control. Inactivation of p53 may be
important in initiation of tumorigenesis in BRCA2 carriers. However,
our results show that two of three of the BRCA2 mutated tumors have
normal p53 and, therefore, inactivation of other integrity control genes
must be involved in these tumors, allowing cells with highly abnormal
chromosomes to go through the cell cycle.
10.
12.
14.
16.
17
18
19
21
22
Acknowledgments
23
We thank the Department of Pathology. National Hospital of Iceland, for
providing samples. We thank the staff at the Department of Pathology for
immunostaining. the staff at Cancer Registry for assistance with population
-,5
data, and the Icelandic Agricultural Institute for FISH facilities. We also thank
Dr. Helga Ögmundsdottir for valuable discussion and comments.
26
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BRCA2 and p53 Mutations in Primary Breast Cancer in Relation
to Genetic Instability
Solveig Gretarsdottir, Steinunn Thorlacius, Rut Valgardsdottir, et al.
Cancer Res 1998;58:859-862.
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