Download Nonrandom Chromosome Alterations inHuman

(CANCER RESEARCH 48, 142-147, January 1, 1988]
Nonrandom Chromosome Alterations in Human Malignant Mesothelioma1
N. C. Popescu,2 A. P. Chahinian, and J. A. DiPaolo
Laboratory of Biology, National Cancer Institute, Bethesda, Maryland 20892 fN. C. P., J.A. D.J, and Department of Neoplastic Diseases, Mount Sinai School of
Medicine, New York, New York 10029 [A. P. C.]
ABSTRACT
Malignant mesothelioma (MM) is a neoplasm closely associated with
asbestos exposure, which has been implicated in 70-80% of the cases.
In this study, nine MM (two fresh surgical specimens, two permanent
cell lines, and five xenografts in nude mice) were examined cytogenetically. Six patients had a known history of asbestos exposure. Seven MM
were chromosomally abnormal, the majority having complex structural
alterations affecting different chromosomes, whereas two fresh surgical
specimens had a normal chromosome constitution. Alterations of chro
mosome 3 were detected in seven cases and changes involving chromo
somes 1 and 7 were observed in six cases. The breakpoints of transloca
tions and deletions on chromosome 1 involved several bands; however,
50% of the breakpoints were near the locations of Blym, L-myc, and ski
protooncogenes. Forty % of the breaks on chromosome 7 involved bands
ql 1.1-11.2 and 20% were at q22, the location of the met protooncogene.
Nonrandom changes on chromosome 3 were interstitial or terminal
deletions, and translocations involving the region pl4-21. The deleted 3p
segment was identifiable as part of a chromosome translocation in one
MM and was apparently lost in the other six. The deletions involving 3p
are either spontaneous or asbestos-induced lesions at vulnerable genomic
sites and are the most common and nonrandom chromosome alterations
observed. Possibly 3p abnormalities are causally related to the develop
ment of this malignancy.
INTRODUCTION
Specific chromosome alterations have been demonstrated in
several forms of human cancer (1). The breakpoints in various
chromosome rearrangements in cancer have been found to
affect a surprisingly limited number of locations and frequently
occur at sites of cellular protooncogenes (2, 3). Furthermore, a
recent statistical analysis showed that the location of 19 of the
26 protooncogenes correspond to one of the 83 bands involved
in primary cancer-specific rearrangements (4). Protooncogenes
can be transposed due to chromosome rearrangements to a new
location near enhancing or promoter sequences causing changes
in protooncogene regulation (5, 6). Burkitt's lymphoma,
reports certain chromosomes were more frequently involved in
alterations, but nonrandom changes were not reported.
In the present study the chromosome constitution of nine
MM from untreated patients, 6 with known exposures to as
bestos, were analyzed. Seven tumors had chromosomally ab
normal clones with varying degrees of complexity in terms of
structural or numerical alterations. Alterations of chromosomes
1, 3, and 7 were the most frequently observed changes. Nonran
dom deletions involving the short arm of chromosome 3 (pi421) were identified in seven cases. Possibly this alteration plays
an important role in the development of MM.
MATERIALS
AND METHODS
After surgical removal, pieces from tumors diagnosed histologically
as MM were placed into RPMI 1640 containing fetal bovine serum
until processed for culturing; similarly, MM transplanted into nude
mice were surgically removed and immersed in medium with serum.
The tumor was minced into small pieces and digested with 0.07%
collagenase for 12 h at 37°Cin a 5% CO2 atmosphere. The suspension
was centrifuged, the cells were washed twice with Hanks' balanced salt
solution, and plated in RPMI 1640 supplemented with 10% fetal calf
serum. When confluent, cultures were subcultured, and 24 or 48 h later
exponentially growing cultures were used for chromosome prepara
tions. Cultures from established cell lines were subcultured 1:4 and
used 24 h later for chromosome preparation. Colcemid (2 x IO7M) was
added 4-12 h before harvesting. The cells were mechanically detached
from the surface of dishes and exposed to 0.075 M KC1 for 15-20 min.
The cells were fixed with a 3:1 mixture of methanohacetic acid; the
fixative was changed three times before making slides. To obtain Gbanding, the chromosome preparations were stained with Giemsa or
Wright stain after trypsin pretreatment. Other slides were processed
for C-banding. For each case 100 conventionally stained metaphases
were counted and at least 25 G-banded karyotypes were examined.
RESULTS
The MM examined included two established cell lines, five
tumors which had been serially transplanted into nude mice,
and two fresh surgical specimens (Table 1). The cell morphol
ogy in culture corresponded to the histológica! type of the
tumor, being epithelial or fibrosarcomatous, or a mixture of
both cell types (Table 1). Cultures derived from transplanted
tumors had variable proportions (5-25%) of host stremai cells,
independent of the number of passages in nude mice. Tumors
transplanted into nude mice preserved the same chromosome
constitutions after extended periods of transplantation as evi
denced by sequential chromosome analysis. For example, one
rising, primarily due to widespread exposure to asbestos which tumor (BG) has the same chromosome constitution after more
has been implicated in 70-80% of the patients with this disease.
than 7 years of serial transplantation in nude mice (11). Simi
Compared to many other forms of cancer, only a small number
larly, one established cell line (JMN) exhibited the same modal
of MM have been cytogenetically examined (7-10). In these
chromosome number after 100 passages in culture (12).
The MM examined had either near diploid or near triploid
Received 7/9/87; revised 9/22/87; accepted 9/28/87.
The costs of publication of this article were defrayed in part by the payment
chromosome numbers. Seven tumors were chromosomally ab
of page charges. This article must therefore be hereby marked advertisement in
normal with both structural and numerical alterations and two
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
' This investigation was supported in part by Grant CA 36283 awarded [to
tumors had a normal karyotype (Table 2). The most frequent
A.P.C.] by the National Cancer Institute, Department of Health and Human
numerical deviations were gain of chromosome 3s in four
Services, Bethesda, M D 20892.
1To whom requests for reprints should be addressed.
tumors (DND, EH, MC, and ES) and losses of chromosome 4s
3The abbreviation used is: MM, malignant mesothelioma(s).
in three tumors (DND, BG, and ES) (Table 2). One or two X
142
chronic myelogenous leukemia, and acute promyelocytic leu
kemia are among the best characterized examples of malignan
cies with specific reciprocal translocations involving protoon
cogenes important for the control of cell growth and tumorigenesis (5, 6). With certain exceptions, chromosome alterations
in solid tumors are very complex compared to those in hematological malignancies (1). The complexity of these changes
may obscure primary changes involved in the process of neoplastic development.
MM3 is a neoplasia of growing concern. Its incidence is
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CHROMOSOME
ABNORMALITIES
Table 1 Origin and morphological
characteristics
IN MM
of malignant
mesotheliomas
in nude
typeEpithelialEpithelialBiphasicEpithelialFibrosar
Age
exposure5759
mice1,666,
CaseJMN*DND*EHCVS*MC*BGrES*FM"KT*OriginAscitesAscitesPleuraltumorPleuraltumorPleuraltumorPleuraltumorPleuraltumorChest
+63
+6667
+4456
1148.5058Cell"
+57
pre
dominantlyepithelialEpithelialBiphasic
wallmassPleuraltumorSexMMMFMFMMMAsbestos
+63
+Passage
" Biphasic denotes a mixture of epithelial and fibrosarcomatous cells.
* Established cell lines were analyzed for chromosomes at culture passage 96-100.
c MM transplanted into nude mice.
'Fresh surgical specimens analyzed at culture passage 1-2 (4-10 days in culture).
Table 2 Cylogenetic data of malignant mesotheliomas
Chromosome'
Case"
Range*
Modal no.
Gain
Loss
Structural abnormalities''
i(dup(5)(pl4-15.3))dup(5)(pl4-15.3)del(7)(q
1) del(3)(p21q21)
3)del(
11.2) del 9(p 13) del( 12)(p?) t(6; 12) (p 11.2;p 1
4.5,812,15,173,19,12
10,14,16,22,15,del(l)(pl
der(7).t(7;HSR
1)(q2 1q23) del(3)(p 14p2 1. 1)(q23) i(3p)del(p 14p2 1)
1.1)der( ?)(pl5;?) del(7)(q22) der(8), t(l;8)(ql l;ql
11.2)der(18),t(?;18)(?;q21)
11)t(8; 11)(q2 1.2;q23) del( 17)(p
i(Xp)del(l)(p32)
19103
del(7)(q22)del(l)(ql2)
del(3)(pl4)
der(4).t(4;?)(q33;?)der(7),t(7;15)(ql
del(3)(pl4) del(3)(ql3.1)
del(7)(q32)der(l).t(l;7)(p22;q22)
l.l;ql 1.2)
del(4)(q33)der(5),t(l;5)(q23;q31)
dir ins(3;?)(p21;?)
8,21,X4,
der(7),t(l;7)(p;q22)der(7),t(7;
t(6;?)(q25;?)
11.2)del(12)(pll.2)t(13;?)del(17)(pll.2)del(l)(p22)
11)(q 11.2q 13) der(7).t( 1;7)(p22; 11.2) del( 10)(p
123,19
20, X
JMNDNDEHVSMCBG48-5265-7670-7844-4671-7541-435172754574425,
13,22,
X,
ES
71-77
73
4,6,14
der(3),t(l;3)(p32;p21)der(7)t(7;12)(pl
t(l;?)(p31;?)
1.2;?)der(10),t(l?;HSR?:10)(p32;q36)
1.2;ql3) i(7p) t(7;?)(pl
11? derl2,t(2:12)(q32;q24.3)
i(lq) der(3).t(3;10)(p21;ql 1.2) del(3)(pl4p21)
t(3;?;5)(qll.2;?;ql3)der(3),t(3;?)(q21;?)
der(4),t(4;l I)(q25;ql3) t(5;?)(q35;?) del(8)(p23)
der( 11),t(4; 11)(q25;q 13) t( 17)(q;?)
inv(9)(pl2ql2)
46-48
FM
46
45-46
KT
46
" Origin of each tumor is shown in Table 1.
'Chromosome number was determined in 100 conventionally stained metaphases.
' Chromosome gain and loss relative to the ploidy level.
d A minimum of 25 G-banded karyotypes was examined. Variable numers (2-10) of unidentified chromosome markers were also present.
chromosomes were missing in two tumors (MC and BG) (Table
2), and tumor cell line JMN had a supernumerary X chromo
some (Table 2). G-banding analysis showed structural clonal
alterations of marked diversity (Table 2); however, structural
alterations involving chromosomes 1, 3, and 7 were most fre
quently observed. Changes of chromosomes 1 and 7 were iden
tified in six cases and alterations of chromosome 3 in seven
cases (Table 2). Alterations of chromosome 1 included terminal
deletions of both the short and long arms, translocations, and
in two tumors an isochromosome, Iq was present (Table 2).
The breakpoints of deletions occurred at different bands on the
short and long arms. However, 50% of the breakpoints affected
the regions p22 and p32 (Table 2). Alterations of chromosome
7 involved deletions and unbalanced translocations with differ
ent chromosomes (Table 2). The breakpoints on chromosome
7 occurred at bands ql 1.1-11.2 and q22; 80% of the breakpoints
identified involved these sites (Table 2). The BG tumor had an
increased number of 7p copies due to the presence of an
isochromosome 7p (Fig. 1), and DND cell line had a translo
cation involving 7p that may contain a homogeneously staining
region (HSR) (Fig. 2).
Deletions of the short arm of chromosome 3 were identified
in seven cases (Table 2). The 3p deletions were either interstitial
(Fig. 2) or terminal (Fig. 3) and occurred at bands 3p 14-21.
Interstitial deletions were observed in two cases and terminal
deletions in five cases were at or above band 3pl4 (Fig. 2). The
entire deleted segment was translocated to another chromo
some in only one tumor, whereas in the remaining cases the
deleted segment was apparently lost. In MC tumor an insertional translocation was identified at 3p 14-21 (Fig. 4). Repre
sentative deletions and translocations are shown in Fig. 5. The
most frequently represented breakpoint on 3p occurred at band
p21 (62%) followed by pl4 (31%) and pl3 (7%). The break
points identified on 3q occurred randomly along the whole arm.
In addition, one tumor (BG) exhibited a large unidentified
abnormal chromosome, with a banding pattern suggestive of a
143
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CHROMOSOME
ABNORMALITIES
IN MM
V
Fig. 1. Karyotype of a hypodiploid cell
from BG tumor transplanted into nude mice.
Although the tumor was derived from a female
patient, only one X chromosome was present.
No normal chromosomes 3 were observed; an
abnormal chromosome resulted from a translocation between chromosomes 1 and 3. A
large abnormal metacentric had a banding pat
tern suggestive of involvement of chromosome
3 and exhibited positive C-band staining on
both arms (inset) indicative of a complex re
arrangement. Four copies of 7p are present.
Arrows, abnormal chromosomes.
ii ifiV li i
i u
ì
U
v*
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3
ft
15
13
14
19
n
l
20
16
17
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22
¡uM'I * um
10--
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13
r -B
19
è1
it
fil
14
15
18
I
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i
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11
12
«;v
21
20
%
s**
»•MM
16
l*
17
51
22
18
ü«
X
Y
« A
M1
rearrangement
(Fig. 1).
li
M1
m KMtÃ-;
Fig. 2. Karyotype of a near-triploid cell
with 71 chromosomes from DND cell line:
arrows indicate abnormal chromosomes. Of six
copies of chromosome 3, only one appeared
normal. The others had either interstitial dele
tions of the short arm (pi4-21) or a terminal
deletion of the long arm. An abnormal chro
mosome 7 may exhibit a homogeneously stain
ing region on the short arm. MI-MS are uni
dentified chromosome markers.
12
11
involving at least a portion of chromosome
M5
3 (p 14-21) identified in seven cases may represent a common
alteration in MM. From a total of 27 cases of MM cytogenetically characterized by banding which include the present ones,
six had a normal diploid constitution, one had a mixture of
normal and abnormal cells (10), whereas the rest were chromosomally abnormal. Fifteen of these MM had abnormalities
of 3p consisting mainly of terminal deletions (7-10). In addi
tion, two out of three unpublished cases also exhibit 3p dele
tions.4
3
DISCUSSION
Analysis of nine MM demonstrates that the majority of these
tumors have numerical deviations and complex structural alter
ations involving various chromosomes. Despite this karyotypic
complexity, structural alterations of chromosomes 1, 3, and 7
were most frequent, and nonrandom deletions of chromosome
4J. Wang-Peng, personal communication.
144
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CHROMOSOME
ABNORMALITIES
IN MM
H U!
Fig. 3. Karyotype of a hypodiploid cell
from the cell line JMN. Several abnormal
chromosomes, including a small metacentric
originating from deletions of both arms of
chromosome 3 are indicated by arrows. Ml
and A/2 are unidentified chromosome markers.
Arrows, abnormal chromosomes.
Ci Hl U
IM
it
13
:i
10
1*
14
15
16
12
11
J •
««
•*
17
».18
»v
Ãi *
19
20
i
21
.. li
22
XX
i
»to'
U
M1
M2
*
Fig. 4. Karyotype of a near-triploid cell
with 74 chromosomes from tumor MC trans
planted into nude mice. An insertional translocation on the short arm of two chromosomes
3 is indicated by arrows. Arrows, abnormal
chromosomes. MI-MS are unidentified chro
mosome markers.
„
**«*u ¡as«UM
-"
"
ftUA
15
HZ**
i
f
12
16
17
18
*«
21
20
19
11
fcift
14
13
10
a ft
22
«è
Y
'
M1 -
-M5
Asbestos exposure and possibly genetic susceptibility are
major contributing factors in the development of MM (13-15).
Nonrandom deletions at 3p may be a reflection of both factors.
Over 90% of the breaks on 3p involved bands p21 and p 14.
The breakage point at pl4 corresponds with the location of an
inducible constitutive fragile site (16, 17) and a region suscep
tible to spontaneous chromosome breakage (18). Chromosomal
fragile site at 3pl4 may have existed in the normal cells of the
patients and were expressed on MM as terminal or interstitial
deletions. Six of the MM examined were derived from patients
with known history of asbestos exposure. Conceivably, exposure
to asbestos fibers may have induced the damage at 3p. In
Chinese hamster cells, asbestos exposure elevated the frequency
of sister chroma) id exchanges, particularly on the larger chro-
145
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CHROMOSOME
ABNORMALITIES IN MM
exhibit specific interstitial deletions on chromosomes 13 and
11, respectively (34-36). An alternative mechanism may involve
the transposition of c-ra/protooncogene to an aberrant location
resulting in structural or functional gene alterations relevant to
the neoplastic development. In situ hybridization analysis of
two renal cell carcinomas demonstrated that c-ra/gene shifted
from 3p25, its normal location (37), to 3pl4 due to an appar
ently terminal 3p deletion (38). The involvement of this protooncogene was described in small cell carcinoma of the lung with
terminal 3p deletions (39, 40).
A relatively large number of hematological malignancies and
solid tumors have deletions at 3p 14-21 (41-54). In MM and
other neoplasms with 3p deletions, the deleted material is
infrequently translocated to another chromosome. The inser
tional translocation identified in one of these MM (MC) is
similar to that described in certain cases of retinoblastoma (55,
56) and Wilms' tumor (57). The molecular alteration caused by
! (
Deletions
Normal
I
I
Translocations
Fig. 5. Deletions and translocations of chromosome 3 identified in seven cases
of malignant mesotheliomas. The first and the second chromosome in the upper
row have interstitial deletions at bands p21 and p 14. respectively. The third
chromosome has a terminal deletion at band p 14. whereas the fourth is deleted
on both arms at p2l and q21. In the lower row. the Tirsi abnormal chromosome
has an insertional translocation al band p21. the second is a translocation 1;3
(p32;p21), and the third chromosome is a translocation 3:10 (p2l;ql 1.2).
the deletion on chromosome 3 is not known in any form of
cancer, however. Whether or not there is a common site of
damage or intraspccific breakage site within 3p 14-21 for each
cancer type will require molecular analysis with appropriate
DNA probes.
mosomes (19), and induced extensive chromosome aberrations
(20). In nontumorigenic Syrian hamster cell lines obtained after
asbestos treatment, a nonrandom trisomy 11 was reported (21).
However, this alteration has been identified in cells transformed
by other carcinogens (22, 23). In vitro exposure of human
mesothelial cells to asbestos caused the formation of abnormal
chromosomes (24), and in our opinion some of these abnormal
chromosomes involved chromosome 3.
Involvement of chromosomes 1 and 7 may also be common
in MM. Changes of chromosome 1 were reported in eight other
cases of MM (9, 10). Alterations of this chromosome are
generally dissimilar (9) and may reflect events associated with
the progression of malignancy (9). However, in this series of
MM, several breakpoints on chromosome 1 were close to the
location ofBlym, (25), L-iwyc (26), or Ski (27) protooncogenes.
Partial or complete trisomy of Iq initially demonstrated in
patients with myeloproliferative disorders (28) were subse
quently identified in a variety of malignancies (29). Trisomy Iq
occurred in two cases of the MM examined as a result of the
formation of an isochromosome Iq. Because chromosome 1
carries several protooncogenes, there is a possibility that im
balance of chromosome 1 arms may be critical for oncogene
dosage in certain neoplasias (6).
The majority of the breakpoints on chromosome 7 clustered
at bands ql 1.1-11.2 at the site of a human ra/-related gene
(30). Several breaks occurred at q22 which includes the region
7q21-31, the location of the met protooncogene (31). In three
cases the short arm of chromosome 17 at band 11.2 rather
distant from the P53 gene was also affected (32). Different
types of chromosome 17 alterations have been reported in five
other cases of MM (9, 10). In two cases, deletions of chromo
some 12pl 1 near the site of K-ras-2 protooncogene (33) were
also identified.
Although no protooncogene had been localized at the critical
sites of breakage on 3p, it is possible that the genetic damage
at these sites represents an important event but not necessarily
a unique alteration responsible for the development of MM.
The region 3p 14-21 may contain one or more suppressor genes
that once deleted unleash the expression of malignancy. This
model could be similar to the recessive acting effect implicated
in the development of retinoblastoma and Wilms' tumors which
ACKNOWLEDGMENTS
We thank Dr. A. Behbehani and Dr. T. Ohnuma for providing JMN
and DND mesothelioma cell lines, respectively.
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Nonrandom Chromosome Alterations in Human Malignant
Mesothelioma
N. C. Popescu, A. P. Chahinian and J. A. DiPaolo
Cancer Res 1988;48:142-147.
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