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Frequent Loss of Heterozygosity on Chromosomes 6q, 11, and 17 in Human
Ovarian Carcinomas1
Je H. Lee, John J. Kavanagh, David M. Wildrick, J. Taylor Wharton, and Mark Blick2
Department of Medical Oncology ¡J.H. L., J. J. A'., D. M. W.], Department of Gynecology [J. T. H'.J, ana Department of Clinical Immunology and Biological Therapy
[\1. B.j, The i 'niversity of Texas A/. D. Anderson Cancer Center, Houston. Texas 77030
ABSTRACT
Recently, tumor-specific alÃ-eleloss has been shown to be an important
characteristic of some tumors. When such loss includes one or more
growth-regulatory genes, it may allow the expression of tumorigenicity.
Using Southern blots, we analyzed normal and tumor DNA samples from
19 ovarian cancer patients, using a series of polymorphic DNA probes
that map to a variety of chromosomal loci. Of 14 informative cases,
tumor-specific allelic loss was observed in nine (64%) at the estrogen
receptor (ESR) gene locus on chromosome 6q. On chromosome 17p at
the DI7S28 and D17S30 loci, allelic losses were also detected in 6 of 8
(75%) and 9 of 14 (64%) cases, respectively. Allelic loss at the HRAS1
gene locus on chromosome lip occurred in 5 of 11 (46%) informative
cases. The relatively high incidence of these allelic losses observed on
chromosome 6q represents the first implication by molecular genetic
analysis of this chromosomal region in a human malignancy, and it thus
appears to be a genetic change specific to ovarian carcinoma. DNA
sequence losses on Up and I7p, also reported for other cancers, may
reflect the presence of tumor- or growth-suppressor genes on these
chromosomes that are important in the genesis of many tumor types,
including ovarian malignancies.
INTRODUCTION
Although ovarian carcinoma is the most frequent cause of
death from gynecological malignancies in the Western World
(1). the histogenesis and biological characteristics of these tu
mors are not well understood. Furthermore, little is known
about potential molecular genetic alterations that may contrib
ute to development of such tumors or to disease progression.
It is now well established that molecular genetic aberrations
can alter the expression of genes and may play a role in
malignant transformation (2). Recent studies indicate that loss
or inactivation of genes at specific chromosomal loci may
contribute to the development of certain childhood tumors such
as retinoblastoma
(3), Wilms' tumor (4), and rhabdomyosarcoma (4). It has been hypothesized that loss of heterozygosity at a specific locus may indicate loss of genetic material
that suppresses the tumor phenotype. Such negative growthregulating genes have been called "tumor-suppressor genes" or
"anti-oncogenes" (5). Because these allelic losses occur not only
in hereditary but also in nonhereditary tumors, it has been
suggested that negative growth-regulating genes are commonly
lost in adult malignancies (6-12). It has been further suggested
that the inactivation of a gene is achieved more readily than its
activation through specific mutations. Consequently, the loss
of an important negative growth-regulating gene may occur
even more frequently during tumorigenesis than activation of a
positive growth-regulating gene (13).
Even though the identification of consistent chromosomal
Received 6/9/89; revised 12/21/89.
The costs 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.
1Supported by an Institutional Research Grant. The University of Texas
M. D. Anderson Cancer Center. Houston. TX. and the Bessie Frisch Memorial
Fund.
2To whom requests for reprints should be addressed, at Molecular Analysis
Incorporated. 8000 El Rio, Houston. TX 77054.
aberrations in fresh ovarian tumors has been very limited,
nonrandom structural or numerical aberrations have been re
ported for several different chromosomes (14-17). We, there
fore, analyzed 19 fresh ovarian cancers for possible tumorspecific allelic loss at 18 different chromosomal loci. Because
of cytogenetic reports of 6q deletions in this disease, we were
particularly interested in the 6q region, as well as in other
chromosomal regions that frequently show allelic loss in other
tumors.
MATERIALS AND METHODS
Patients and Tissues. Primary and metastatic malignant ovarian
tumors from a total of 19 patients at the M. D. Anderson Cancer
Center (Houston, TX) were obtained from surgical pathology immedi
ately after surgery'- The fresh solid tissues were dissected free of fat and
necrotic tissue. The specimens were stored at -70°C until DNA was
extracted. The histológica! diagnosis of the tumors studied was estab
lished by the Department of Pathology, from paraffin-embedded sec
tions. The histológica! grading was performed according to a system
described by Mauch et al. ( 18). Peripheral blood samples were obtained
from the same patients from whom the tumor tissues were procured.
Stages of disease were assigned according to the classification scheme
accepted by the general assembly of International Federation of Gyne
cology and Obstetrics (19).
Preparation of High Molecular Weight DNA. Tumor tissue, pulver
ized in liquid nitrogen as described (20), and lymphocytes from periph
eral blood samples were lysed in EDTA/sodium dodecyl sulfate solu
tion, proteinase K digested, phenol/chloroform extracted, ethanol pre
cipitated, resuspended in sterile water, and spectrophotometrically
quantified as previously described (20).
Allelic Loss Analysis. Fifteen ^g of high molecular weight DNA were
digested to completion with the appropriate restriction endonuclease
as recommended by the supplier (Bethesda Research Laboratories,
Gaithersburg, MD), size fractionated in a 0.8-1.2% agarose gel, dena
tured, neutralized, and transferred to a nylon filter (21). Hybridization
to oligo-primed "P-labeled (22) probes was conducted at 42°Cfor 4872 h. The filters were then washed at 60°Cfor 60 min in 0. Ix saline
sodium citrate (SSC = 0.15 Msodium chloride, 0.015 M sodium citrate)
containing 0.1% sodium dodecyl sulfate and autoradiographed at
-70°Cusing intensifying screens. The following probes and restriction
enzymes were used: chromosome 1, pAT3 (Pstl) (23); chromosome 2,
pYNZIS (Taq\) (24) and IMR-6 (£coRI)(25); chromosome 5, pHGRl
(Bcl\) (26); chromosome 6, pHHH157 (BamHl) (27), pHM2.6 (EcoRl)
(28). and pOR3 (Pvull) (29); chromosome 7, HER-A64-1 and HERA64-3 (Hiniilll) (30); chromosome 11, c-Ha-rasl (ßamHI) (31),
pHlNS300 (fcoRI) (32), and SS6 (BamHl) (33); chromosome 12,
pSW480-cDNA-5(7a<7l) (34); chromosome 17, pYNH37.3 (Taql)(35),
pYNZ22 (Mspl or BamHl) (36), and cEFD52 (Pvull) (37); chromo
some 19, pHP450 (Sad) (38); and chromosome 22, L335 (Hindlll)
(39).
Patients' constitutional DNA samples that were informative, i.e.,
heterozygous, for a given marker displayed restriction fragments cor
responding to each of two alÃ-elesin the resultant autoradiograph. Allelic
loss from the matched tumor DNA was indicated by the disappearance
of restriction fragments specific for either alÃ-ele.
RESULTS
Loss of heterozygosity occurred frequently at several chro
mosomal loci in ovarian carcinomas. We examined a total of
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LOSS OF HETEROZYGOSITY
18 loci from 10 different chromosomes. Representative results
are displayed in Figs. 1-3. Loss of heterozygosity was observed
at loci on seven different chromosomes: chromosomes 2, 6, 7,
11, 17, 19, and 22. The frequency of alÃ-eleloss at individual
loci ranged from one of eight (13%) at the MYB locus on
A)
Ch.Gq
Case
10
case
12
N T
N T
B)
kb
Ch. 11p
Case Case
10
11
N T N T kb
-1.5
-8.8
--6.5
1.0
0.7
ESR
(Pvull)
C)
HRAS1
(BamHI)
Ch. 17p
Case
Case
11
12
N T
N T
D)
kb
Ch. 17p
Case Case
4
16
N T N T
kb
- 2
D17S28
(Taql)
D17S30
(BamHI)
Fig. 1. Southern blot analysis demonstrating loss of heterozygosity on chro
mosomes 6q (A, eases 10 and 12), 1Ip (B, cases 10 and II), and 17p (C. cases 11
and 12; D, cases 4 and 16) in patients with ovarian carcinomas. DNA was isolated
from tumors (7") and corresponding normal lymphocytes (A7).The loci analyzed
and restriction endonucleases used are indicated under each panel, ESR (Pvull),
HRAS1 (BamHI), D17S28 (Taql), and D17S30 (Mspl or BamHI), respectively.
Allelic forms are designated to the left of each panel: a is the longer and b the
shorter fragment. The size in kilobases of each alÃ-eleis given to the right of each
panel. *, the allelic fragment lost in tumor DNA sample in each panel. In this
figure, cases 10, 11, and 12 show loss of alÃ-eleson more than one chromosome.
IN OVARIAN CARCINOMAS
chromosome 6q to six of eight (75%) at the DI7S28 locus on
chromosome 17p (Table 1). Loss of heterozygosity at one or
more loci was detected in 75% (14 of 19) of ovarian carcinomas.
The incidence of loss of heterozygosity was remarkably high on
chromosomes 6q (64% at the ESR gene locus), 17p (75 and
64% at the D17S28 and D17S30 loci, respectively), and lip
(46% at the H RASI gene locus).
Allelic Losses on Chromosome 6. To characterize allelic loss
on chromosome 6, we used three different polymorphic DNA
probes: one for the short arm (D6S29 locus) and two for the
long arm (MYB and ESR loci). Loss of heterozygosity occurred
at high frequency in the terminal region of the long arm of
chromosome 6, the area to which the ESR gene maps (Table 1
and Fig. 3). The frequencies of loss of heterozygosity were
similar in both primary tumors (63%) and metastatic lesions
(67%) at the ESR locus. Of six individuals heterozygous at both
the ESR and MYB loci, five (83%) showed an allelic loss at
only the ESR locus. A polymorphic DNA probe (pHHH157)
for the D6S29 locus on the short arm detected nine informative
individuals, none of whom revealed an allelic loss.
Allelic Losses on Chromosome 17. On chromosome 17p at
the DI 7S28 and Dl 7S30 loci, loss of an alÃ-elewas observed in
6 of 8 (75%) informative individuals and in 9 of 14 (64%)
informative patients, respectively (Table 1 and Fig. 2). Among
14 samples that showed loss of heterozygosity on the short arm
of chromosome 17 (D17S28 or D17S30) and that also were
informative at the D17S26 locus on the long arm, six (43%)
showed concurrent allelic losses. Of eight samples from inform
ative individuals who revealed ESR gene allelic loss and also
were informative at a chromosome 17p locus (DI7S28 or
D17S30), five (63%) showed simultaneous allelic losses on both
chromosomes.
Allelic Losses on Chromosome lip. Among the 19 normal/
tumor DNA sample pairs we examined, 11 (58%) individuals
were heterozygous and thus informative. In 5 of these 11 (46%)
cases, loss of heterozygosity occurred. The fact that we did not
observe any allelic loss at the INT2 locus (on 1Iq) suggests that
the HRAS1 allelic loss was largely due to subchromosomal
structural changes.
Allelic Losses on Other Chromosomes. To determine whether
these restriction fragment length polymorphism allelic losses
were specific for chromosomes 6q, 11p, and 17p in ovarian
Case 15
Kb
Fig. 2. Case 15 has a terminal deletion with
loss of an alÃ-eleat DI7S28 but retained geno
type at Dl 7S30 in tumor tissue. Similarly, case
19 has an interstitial deletion with loss of one
alÃ-eleat D17S30 but retained genotype at
DI 7S28. These two loci are separated by only
2 centimorgans at the tip of 17p. *, the allelic
fragment lost in tumor DNA sample in each
panel.
NT
NT
Kb Kb
7.8-
4.4-
D17S28 D17S30
(Taql) (BamHI)
D17S28 D17S30
(Taql) (BamHI)
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LOSS OF HETEROZYGOSITY IN OVARIAN CARCINOMAS
Case 13
Kb
2.6Fig. 3. Cases 13 and 14 have partial dele
tions with loss of one alÃ-eleat ESK locus
(6q24-27) in tumor tissue but retained geno
type at MYB locus (6q22-23). *. the alleile
fragment lost in tumor DNA sample in each
panel.
NT
NT
14
Kb Kb
NT
NT
Kb
-1.5
1.5-
«* -1.0
*
•0.7
MYB
(EcoRI)
ESR
(Pvull)
carcinomas and not simply a result of widespread random losses
of genetic material, we employed other DNA probes capable of
detecting restriction fragment length polymorphisms at 14 ad
ditional loci on chromosomes 1, 2, 5, 6, 7, 11, 12, 19, and 22
(see Table 1). Among these, at each chromosomal locus where
constitutional heterozygosity was observed, heterozygosity was
also maintained in the matched tumor tissue in most cases.
DISCUSSION
The demonstration of loss of heterozygosity at the HRAS1
locus, as well as other lip markers, in a variety of human
cancers (reviewed in Ref. 40) including ovarian carcinomas (20)
suggests that their development or progression may involve loss
or inactivation of normal genes on lip. Previously we reported
that tumor-specific alÃ-eleloss occurs at the HRAS1 locus on
chromosome 1Ip in 50% of ovarian carcinomas (four primary
tumors, eight métastases,and five ascites samples) (20). The
current study extends that observation at about the same fre
quency (46%) to an expanded sample, cases 1-9 in Table 1,
which includes five additional primary ovarian carcinomas, and
cases 10-19 in Table 1, which includes two additional métas
tases.
More significantly, our study clearly shows that tumor-spe
cific alÃ-eleloss occurs in ovarian carcinoma at an even higher
frequency for markers on chromosomes 6q (64% at ESR) and
17p (75% at D17S28, 64% at D17S30) than for lip. This is
the first report of tumor-specific alÃ-eleloss from chromosomes
6 and 17 in ovarian carcinomas, suggesting the potential exist
ence on these chromosomes of tumor- or growth-suppressor
genes whose loss promotes this disease.
Deletion of part of chromosome 6q has been observed in
several cytogenetic studies of ovarian carcinoma (14-17), which
prompted us to investigate the long arm of chromosome 6 at
the molecular level. Our finding of such a high incidence of
tumor-specific alÃ-eleloss in both primary and metastatic tumor
tissues at the ESR gene locus (6q24-q27) (41) suggests that
this loss might be a genetic event specific to ovarian cancer.
Because 6q deletions have been observed cytogenetically in early
gynecological malignancies, including a noninvasive ovarian
carcinoma (42) and an ovarian granulosal cell tumor (43) (a
borderline malignancy), loss of DNA sequences from 6q might
MYB
(EcoRI)
• -0.7
ESR
(Pvull)
indicate that inactivation of a tumor- or growth-suppressor
locus located there is an earlier event in ovarian tumorigenesis.
However, this hypothesis needs to be tested by looking for
tumor-specific 6q alÃ-eleloss in the DNA of such early and
borderline cancers before trying to classify such genetic changes
as early or late events.
The fact that the more distal ESR alleile marker on 6q is lost
more frequently (65%), compared to the more proximal MYB
marker (13%), suggests that the ESR locus is closer to the
region possibly uniquely lost in ovarian cancer. This notion is
supported by the fact that the only tumor sample showing loss
of heterozygosity at the MYB locus had concordant loss of
heterozygosity at the ESR locus. Of further interest, other
investigators in our laboratory have analyzed breast cancer
DNA samples from 15 informative patients and observed an
ESR gene allelic loss in tumor DNA from only one patient,
demonstrating that loss of 6q sequences is not common to all
cancer types.3
In addition to the cytogenetic reports of chromosome 6q
deletions, an isochromosome for the long arm of chromosome
17 (i[17q]) was also reported in early gynecological malignan
cies, indicating possible deletion of the short arm of chromo
some 17 (42). Our results suggest that the mechanism of alÃ-ele
loss from chromosome 17p resulted from partial or total loss
of chromosome 17, because in 6 of 14 (43%) instances there
were concurrent alÃ-elelosses at both short and long arm loci.
Because others have shown that tumor-specific allelic loss from
chromosome 17 occurs in several different tumor types (12,
44-46) and because our data imply frequent chromosome 17
losses in ovarian cancer, genes on this chromosome might be
involved in a cooperative role with other genes on 6q (or 1Ip)
in mechanisms of tumorigenesis or disease progression. Fur
ther, the high incidence of concordant allelic losses from chro
mosomes 6q and 17p in 7 of 14 (50%) patients informative for
both loci was, in our study, very impressive. Within the limits
of the present study, it would be very difficult to determine the
timing of these allelic losses from different chromosomes. The
target genes in ovarian cancer may be located on both chro
mosomes.
In conclusion, whereas alÃ-eleloss from chromosome 1Ip has
3 E. H. Koh et al., personal communication.
2726
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LOSS OF HETEROZYGOSITY
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IN OVARIAN CARCINOMAS
been linked to at least eight cancer types and chromosome 17p
alÃ-eleloss to three different neoplasms (see Ref. 40), loss of
chromosome 6 sequences has not been associated previously
with any cancer. This makes it more likely that the 6q allelic
losses uniquely observed here for ovarian cancer indicate the
presence on 6q of a putative tumor- or growth-suppressor gene
specific to this cancer.
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ACKNOWLEDGMENTS
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We are indebted to Y. Nakamura for kindly providing probes
pYNZIS, pYNH37.3, pYNZ22, and cEFD52; to C. Dickson for SS6;
•«i(for
to G. I. Bell for pHINS300; to D. Stehelin for pHM2.6; to M. Hansen
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for valuable advice and critical review of the manuscript; to Leslie
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Wildrick for editorial assistance; and to Maricela Malbrough for typing
WithèRE1.2.3.4.S.6.7.8.9.10.11.12.13.14.15.16.17.18.19.20.
the manuscript.
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LOSS OF HETEROZYGOSITY
IN OVARIAN CARCINOMAS
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1990 American Association for Cancer Research.
Frequent Loss of Heterozygosity on Chromosomes 6q, 11, and
17 in Human Ovarian Carcinomas
Je H. Lee, John J. Kavanagh, David M. Wildrick, et al.
Cancer Res 1990;50:2724-2728.
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