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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 3007-3010
Characterization of Nonrandom Chromosomal Gains and Losses in
Multiple Myeloma by Comparative Genomic Hybridization
By
Juan C. Cigudosa,
Pulivarthi H. Rao,
M. Jose Calasanz,
M. Dolores Odero,
Joseph Michaeli,
Suresh C. Jhanwar, and
R.S.K. Chaganti
From the Cell Biology and Genetics Program and the Departments of
Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center,
New York, NY; and the Department of Genetics, University of Navarra,
Pamplona, Spain.
 |
ABSTRACT |
Clonal chromosomal changes in multiple myeloma (MM) and related
disorders are not well defined, mainly due to the low in vivo and in
vitro mitotic index of plasma cells. This difficulty can be overcome by
using comparative genomic hybridization (CGH), a DNA-based technique
that gives information about chromosomal copy number changes in tumors.
We have performed CGH on 25 cases of MM, 4 cases of monoclonal
gammopathy of uncertain significance, and 1 case of Waldenstrom's
macroglobulinemia. G-banding analysis of the same group of patients
demonstrated clonal chromosomal changes in only 13 (43%), whereas by
CGH, the number of cases with clonal chromosomal gains and losses
increased to 21 (70%). The most common recurrent changes detected by
CGH were gain of chromosome 19 or 19p and complete or partial deletions
of chromosome 13. +19, an anomaly that has so far not been detected
as primary or recurrent change by G-banding analysis of these tumors,
was noted in 2 cases as a unique change. Other recurrent changes
included gains of 9q, 11q, 12q, 15q, 17q, and 22q and losses of 6q and 16q. We have been able to narrow the commonly deleted regions on 6q and
13q to bands 6q21 and 13q14-21. Gain of 11q and deletion of 13q, which
have previously been associated with poor outcome, can thus be detected
by CGH, allowing the use of this technique for prognostic evaluation of
patients, without relying on the success of conventional cytogenetic
analysis.
| |
INTRODUCTION |
MULTIPLE MYELOMA (MM) is a malignancy of
clonal plasma cells with a wide variability in clinical features,
responses to treatment, and survival times among patients. Although it
accounts for 10% of hematologic malignancies, it represents less than
1% of chromosomally abnormal hematologic disorders
reported.1-6 This lack of correlation between incidence and
information on chromosomal changes in MM is due to the low mitotic
index of plasma cells that reduces the availability of analyzable
metaphases. Clonal chromosomal changes have been detected in
approximately 40% of MM cases; and they show clustering of
rearrangement breakpoints at bands 14q32, 16q11, and
22q11.6 In addition, duplication of the long arm of
chromosome 1 and deletions affecting the long arms of chromosomes 6 and
13 have been frequently noted.2-6
The usefulness of karyotypic analysis in the prognostic evaluation of
MM patients has been recently studied.5-7 Univariate and
multivariate survival analyses have shown that hypodiploidy, partial or
complete deletion of chromosome 13, and abnormalities of 11q and 22q
have been significantly associated with an adverse outcome.7,8 However, the potential value of cytogenetic
analysis is limited to the subset with karyotypic data. The molecular
cytogenetic technique comparative genomic hybridization (CGH) enables
identification of chromosomal copy number changes in tumors without the
need to perform conventional cytogenetic analysis.9-11 This
approach can thus be applied to all MM cases to obtain the
prognostically relevant chromosome gain/loss information. We used CGH
to analyze chromosome copy number changes in a panel of 30 patients
with either MM, monoclonal gammopathy of uncertain significance
(MGUS), or Waldenstrom's macroglobulinemia (WM). We found that 70% of the cases showed clonal changes that included aberrations previously noted to be of prognostic value as well as those so far not
identified as recurring changes in MM.
| |
MATERIALS AND METHODS |
Tumor ascertainment and cytogenetics.
Bone marrow samples were collected from 30 patients, 25 with MM, 4 with
MGUS, and 1 with WM. Of these, 17 were ascertained at the University
Clinic of Navarra (UCN; Pamplona, Spain), and the remaining 13 were
ascertained at the Memorial Sloan-Kettering Cancer Center (MSKCC; New
York, NY). The samples were derived from 22 at diagnosis and 8 previously treated patients (Table 1). The
ages of the patients ranged from 33 to 77 years, with a median of 59 years. Among the 30 patients, 16 were women and 14 were men.
Cytogenetic analysis at UCN included unstimulated short-term and
B-cell-stimulated 48-hour cultures,12 whereas cytogenetic
analysis at MSKCC was performed on unstimulated short-term cultures of
biopsy samples. G-banding by standard procedures was used in both
laboratories. Karyotypes of cases no. 16, 17, and 19 were previously
reported.6
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Table 1.
Treatment Status, Percentage of Plasma Cells in Bone
Marrow, and G-Banded and CGH Karyotypes of Tumor Samples Studied
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CGH.
Tumor DNA was extracted from bone marrow samples and subjected to CGH
analysis essentially as described.11 Briefly, the tumor
(test) and normal (reference) DNAs were labeled by nick-translation with fluorescein-12-dUTP and Texas Red-5-dUTP (NEN-DuPont, Boston, MA),
respectively. Equal amounts (200 ng) of tumor and normal DNAs were
coprecipitated with 10 mg of human Cot-1 DNA (GIBCO/BRL, Gaithersburg,
MD) and resuspended in the hybridization mix before in situ
hybridization to human metaphase chromosome spreads prepared from
phytohemagglutinin-stimulated lymphocytes from normal individuals. After hybridization, the slides were washed and the chromosomes were
counterstained with 4,6-diamino-2-phenylindole (DAPI) to enable
identification of the chromosomes. Fluorescent hybridization signals
and DAPI-staining patterns were captured with a cooled charge-coupled
device (CCD) camera (Photometrics, Tuscon, AZ) attached to a Nikon
Microphot-SA microscope and processed using an image analysis system
(Quips, Vysis, IL). The software performed a calculation of the green
(tumor DNA) to red (normal DNA) fluorescent ratios along the length of
each chromosome. The average of readings from eight chromosomes were
graphed for each chromosome and compared with the profile for the same
chromosome in a reference DNA/reference DNA hybridization to set the
boundaries of gain and loss. Ratios greater than 1.20 and less than
0.80 were considered to represent chromosomal gain and loss,
respectively. These threshold levels were tested as reported previously
by us.12 CGH detects DNA sequence copy number relative to
the average copy number in the tumor but not the ploidy level of the
tumor.10 Therefore, the ploidy level of the tumor in
this study was determined by conventional cytogenetics (Table 1).
Chromosomal regions near the centromeres of 1, 9, 13-16, 21, and 22 were not scored for CGH analysis because of the highly repeated
sequences in these regions. In the present study, control DNA was
always obtained from a male donor, and the ratios for gains and
losses of sex chromosomes were appropriately adjusted when test DNA was
not matched. Recurrence of a change was defined by its presence in 2 or
more tumors.
| |
RESULTS |
G-banded cytogenetic analysis.
Thirteen of the 30 (43%) patients showed clonal chromosomal
abnormalities by G-banding (Table 1). Karyotypes were hyperdiploid (30%), pseudodiploid (47%), or hypodiploid (23%). A 14q+ marker chromosome was detected in 5 cases (38%); in 3 of them, it was derived
from the t(11;14)(q13;q32) translocation. Among the remaining chromosomal abnormalities seen, recurrent changes comprised del(11) and
del(16) in 3 cases each and  X and +1q in 2 cases each.
CGH analysis.
The proportion of patients with chromosomal aberrations
increased to 21 by CGH (70%; Table 1). The clonally abnormal cases included 18 MM, 2 MGUS, and the single WM cases. The proportion of bone
marrow plasma cells in cases that were clonally abnormal by CGH ranged
between 16% to 98%. Overall, 10 chromosomal changes were recurrent
(Fig 1). The most frequent changes were complete or
partial deletions of chromosome 13 and gain of chromosome 19 or 19p
(30%). Other frequent losses were complete or partial deletions of 6q
(13%) and 16 (17%), with the commonly deleted regions spanning bands 6q21 and 13q14-21 (Fig 1). The partial karyotypes displayed in
Fig 2 show representative losses of 13q, 6q, and 16q.
None of the cases studied showed any of the recurrent losses detected to be unique aberrations (Table 1). Recurrent gains included partial
gains of 11q (20%) and, less frequently (~10%), gains of 9q, 12q24,
15q23-qter, 17q22-24, and 22q. Among gains, 2 were unique changes: +19
in cases no. 4 and 7 and +11q13-21 in case no. 30. Representative
partial karyotypes of cases no. 18 and 26, showing +9, +11q, and +15,
are shown in Fig 2.
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| Fig 1.
Partial ideogram showing recurrent DNA copy number
changes detected by CGH in the MM cases studied. Vertical lines on the right and left of each chromosomal ideogram identify gains and losses,
respectively. The proportions of cases showing each of the changes are
noted. For chromosomes 6, 9, 11, 13, 15,17, and 22, the lines delineate
only the commonly gained or deleted regions. For chromosome 19, both
complete and partial gains represented were recurrent.
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View larger version (53K):
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| Fig 2.
Partial CGH karyotypes (left) and corresponding ratio
profiles (right) observed in cases no. MM18 and MM26. Case no. MM18 showed deletions of chromosomes 6q21 and 13q14-22 and gains of 9q and
chromosome 15. Case no. MM26 showed gain of 11q and loss of 16q.
Hybridized tumor DNA was visualized via fluorescein isothiocyanate (green) and control DNA was visualized via Texas Red (red). The averaged green to red fluorescent signal ratio along the length of the
chromosome is shown. The blue line in the ratio profile represents the
mean of 8 to 10 chromosomes and the yellow line represents the standard
deviation. The vertical red and green bars on the right of the ideogram
indicate threshold values of 0.8 and 1.20 for loss and gain,
respectively.
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Comparison of abnormalities detected by G-banding versus CGH in the
cases in which both types of data were available (Table 1) showed a
variation in the degree of concordance between the two methods of
analysis. A subset of 6 cases (1, 2, 3, 17, 26, and 30) showed a high
level of concordance between the abnormalities detected by the two
techniques; in contrast, the remaining 7 cases (6, 7, 9, 16, 19, 22, and 27) showed discrepancy in almost every single abnormality. In
addition, the types of abnormalities detected in different proportions
of cases also seemed to depend on the technique used. Thus,
rearrangements of 11q were observed by G-banding in 5 of the 6 cases
that showed this anomaly by CGH; in contrast, only 1 case with abnormal
karyotype by G-banding showed monosomy 13 compared with 9 cases in
which this anomaly was detected by CGH.
| |
DISCUSSION |
Cytogenetic analysis of MM and related disorders has so far been
hampered by the low proliferative activity of plasma cells, with
abnormal karyotypes having been noted in 30% to 50% of
cases.2-6,13 Interphase fluorescence in situ
hybridization studies using centromeric probes have shown
numerical chromosomal aberrations in 80% to 90% of cases, suggesting
that clonal chromosomal abnormalities are frequent in these
disorders.14,15 Therefore, we reasoned that application of
CGH would provide new information on gains and losses of chromosomal
regions in MM and related disorders, because this technique is
performed using small amounts of DNA rather than cultured cells. In the
present study, 70% of tumors showed clonal chromosomal changes. Thus,
CGH was more sensitive in detecting chromosomal copy number changes
than conventional G-banding. The 6 cases (12, 13, 20, 21, 25, and 29)
that did not show clonal chromosomal abnormalities by CGH shared some
features: they were obtained at diagnosis, the plasma cell infiltration in them was either less than 30% or they were diagnosed as MGUS, and
they showed normal karyotype by G-banding analysis. We have previously
described a similar association between absence of cytogenetic
aberrations and lack of prior treatment or less than 30% plasma cell
infiltration.6,12 A possible explanation for this
association, and thus the trend seen in the CGH results, is that at the
early stages of the disease, genetic changes may not involve
recognizable chromosomal alterations. However, cases no. 10, 11, and
24, which presented a high proportion of plasma cells in the bone
marrow, are not compatible with this explanation. These tumors may
carry a chromosomal translocation(s) and/or small deletion
(<2 kb) that cannot be detected by CGH.
Overall, we observed a variable correlation between the results of
G-banding and CGH analyses. Thus, we noted 10 recurrent changes (Fig
1), all of which have been previously described by us and others in
MM.1-6,13 We have identified 9 cases (30%) that showed
total or partial gains of chromosome 19 by CGH. This change has been
one of the most frequent in our series and it has been noted as a
unique anomaly in 2 cases. However, by G-banding, this change was
detected only in 2 cases. The significance of this trisomy in MM
development remains to be elucidated. Partial loss of chromosome 13 (also seen in 30% of the cases) was missed by conventional cytogenetic
analysis in 8 of the 9 cases in which it was detected by CGH. We found
some other discrepancies also in the results of the 13 cases in which
both techniques were successful (Table 1). These discrepancies can be
explained by the fact that G-banding analysis is based on the study of
chromosomes of the clone proliferating in vitro, which may or may not
be the predominant tumor clone, and hence may or may not be
representative of the CGH result.
The CGH analysis allowed us to narrow the chromosome 13 deletion to a
common region that spans the bands 13q14-21. The same region has
previously been reported to be frequently deleted in chronic
lymphocytic leukemia (CLL) and in 1 case of
MM.16-18 Therefore, the candidate tumor-suppressor gene
proposed in CLL and other lymphoid malignancies may be involved in the
genesis and/or progression of MM as well. In the same way,
deletions affecting 6q have been reported in MM and other lymphoid
malignancies.19 We have identified the common region of
deletion at 6q21, a region that has also been identified in a subset of
non-Hodgkin's lymphoma by G-banding and LOH studies.20
Finally, 16q loss has been observed in a subset of patients in our
series; del(16)(q22) has previously been reported as unique change in
MM.6 Therefore, candidate tumor-suppressor genes at 6q21
and 16q22 may be of importance in the pathogenesis of MM.
Using CGH, we have shown that 70% of MM biopsies present recurrent
chromosomal gains and losses. These included deletions of 13q and gains
of 11q that have previously been associated with a poor
outcome.7,8 These abnormalities can be easily detected by
CGH, without relevance to G-banding analysis, thus providing a valuable
approach to identifying prognostically significant lesions using small
amounts of DNA from nondividing cells.
| |
FOOTNOTES |
Submitted August 11, 1997;
accepted December 1, 1997.
Supported by Grants No. CA-34775 and CA-66999 from the National
Institutes of Health/National Cancer Institute (to R.S.K.C.).
Address reprint requests to R.S.K. Chaganti, PhD, Memorial
Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
