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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 234-240
Chromosomal and Gene Amplification in Diffuse Large B-Cell Lymphoma
By
Pulivarthi H. Rao,
Jane Houldsworth,
Katerina Dyomina,
Nasser Z. Parsa,
Juan C. Cigudosa,
Diane C. Louie,
Leslie Popplewell,
Kenneth Offit,
Suresh C. Jhanwar, and
R.S.K. Chaganti
From the Cell Biology Program and the Departments of Pathology and
Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY.
 |
ABSTRACT |
Chromosomal translocations leading to deregulation of specific
oncogenes characterize approximately 50% of cases of diffuse large
B-cell lymphomas (DLBL). To characterize additional genetic features
that may be of value in delineating the clinical characteristics of
DLBL, we studied a panel of 96 cases at diagnosis consecutively ascertained at the Memorial Sloan-Kettering Cancer Center (MSKCC) for
incidence of gene amplification, a genetic abnormality previously shown
to be associated with tumor progression and clinical outcome. A subset
of 20 cases was subjected to comparative genomic hybridization (CGH)
analysis, which identified nine sites of chromosomal amplification (1q21-23, 2p12-16, 8q24, 9q34, 12q12-14, 13q32, 16p12, 18q21-22, and
22q12). Candidate amplified genes mapped to these sites were selected
for further analysis based on their known roles in lymphoid cell and
lymphoma development, and/or history of amplification in
tumors. Probes for six genes, which fulfilled these criteria, REL (2p12-16), MYC (8q24), BCL2 (18q21),
GLI, CDK4, and MDM2 (12q13-14), were used in a
quantitative Southern blotting analysis of the 96 DLBL DNAs. Each of
these genes was amplified (four or more copies) with incidence ranging
from 11% to 23%. This analysis is consistent with our
previous finding that REL amplification is associated with
extranodal presentation. In addition, BCL2 rearrangement
and/or REL, MYC, BCL2, GLI,
CDK4, and MDM2 amplification was associated with
advanced stage disease. These data show, for the first time, that
amplification of chromosomal regions and genes is a frequent phenomenon
in DLBL and demonstrates their potential significance in
lymphomagenesis.
| |
INTRODUCTION |
B-CELL DIFFUSE LARGE cell lymphomas
(DLBLs) are clinically and genetically heterogeneous. Approximately
50% of patients relapse after treatment and succumb to recurrent
lymphoma.1,2 The frequently recurring chromosomal
translocations, t(3;14)(q27;q32), t(8;14)(q24;q32), and
t(14;18)(q32;q21), have been shown to characterize genetic subsets,
which together make up approximately 50% of DLBLs.3 In
these translocations, the expression of BCL6 (3q27),
MYC (8q24), and BCL2 (18q21) genes is deregulated as a
result of their juxtaposition to the IG genes.3
However, the genetic basis of the clinical heterogeneity of DLBL is
poorly understood. One genetic lesion frequently associated with
progression and clinical outcome of diverse tumor types is gene
amplification.4 Although sporadic cases of DLBL with gene
amplification detected by cytogenetic and/or molecular genetic
methods have been reported,5-7 the incidence or biologic
significance of gene amplification in DLBL has not been studied in
detail. Recently, by comparative genomic hybridization (CGH) analysis
of a case of DLBL with double minute chromosomes (dmins), we identified
high level amplification of the chromosomal region
2p13-15.6 Following a Southern blotting-based candidate gene approach analysis, we showed that the REL proto-oncogene, mapped to this chromosomal region, is amplified in this single tumor,
as well as in 23% of cases of DLBL.6 To compare gains and
losses of DNA in DLBLs with a t(14;18)(q32;q21) translocation to those
without an IG gene site-associated translocation, we undertook
detailed CGH and follow-up candidate gene analysis of a cohort of
previously untreated B-cell non-Hodgkin's lymphoma (NHL) specimens
diagnosed as DLBL by the International Lymphoma Study
Group (ILSG) classification.8 We identified nine
sites of chromosomal amplification and frequent amplification of
REL, MYC, BCL2, GLI, CDK4, and
MDM2, and found that gene amplification was associated with
advanced stage disease at diagnosis.
| |
MATERIALS AND METHODS |
Tumor specimens.
A subset of 96 at diagnosis B-cell NHL biopsy specimens histologically
classified as DLBL according to ILSG criteria (diffuse large cell,
diffuse mixed small, and large cell, immunoblastic),8 were
selected for this study from our ongoing prospective ascertainment of
consecutive NHL cases for genetic and clinical analyses, initiated in
1984 and previously described in detail.9,10 None of the cases belonged to the subset primary mediastinal (thymic) large B-cell
lymphoma (PMLBL) or showed evidence of follicularity. Of the 96 cases,
78 were previously studied for REL amplification.6
Cytogenetic analysis and CGH.
Karyotypic analysis using G-banding after conventional
methods was attempted on each biopsy ascertained. CGH analysis of a subset of 20 tumors with G-banding karyotype data was performed on DNA
extracted from frozen tumor tissue as described6 using the
Quantitative Image Processing System (QUIPS, Vysis, IL). For each
hybridization, a minimum of five metaphases was analyzed and green to
red fluorescence ratio profiles for eight to 10 chromosomes exhibiting
comparable levels of fluorescence intensity were normalized to standard
length and combined statistically to display mean and 95% confidence
intervals of the ratio. Chromosomal imbalances were detected on the
basis of the ratio profiles deviating from the balance value of green
to red ratio of 1.0. Ratio values of 1.20 and 0.80 were used as upper
and lower thresholds to define gains and losses,
respectively.6 Regions near the centromeres of chromosomes
1, 9, 13-16, 21, and 22 were not scored in the CGH analysis because of
the highly repeated nature of DNA in these sites. High level
amplification was defined as occurrence of fluorescence intensity
values in excess of 2.0 and strong localized fluorescein isothiocyanate
(FITC) signal at the chromosomal site. For chromosomal definition of such regions of high level amplification, the peaks of
the ratio profiles were compared with the corresponding
4 ,6-diamidino-2-phenylindole (DAPI) banding of individual
chromosomes. Chromosomal or subchromosomal gain or loss was considered
recurrent if detected in two or more tumors by G-banding or CGH.
Southern blot analysis and determination of gene copy number.
Southern blotting using probes for the REL,
MYC, BCL2, GLI, CDK4, and MDM2 genes
and the restriction fragment length polymorphism (RFLP) probe D2S48
(control of copy number) was performed on the DNA isolated from
snap-frozen biopsies of the entire panel of 96 tumors, as described
recently by us, to determine their gene copy number.6 In
addition, BCL2 gene rearrangements were ascertained from the
same hybridization filters using appropriate probes as described by
us.11 All the probes used were as described
previously.5,6,11,12 A probe for CDK4 was generated
by polymerase chain reaction (PCR).
Clinical correlation analysis.
To analyze the effect of genetic alterations taken in aggregate, a
score was computed for each case with one point given for each of the
following alterations: BCL2 rearrangement, or  4 copies of
REL, MYC, BCL2, GLI, CDK4, or
MDM2 determined as described above. The mean score for these
genetic variables was compared in groups with different clinical
features (eg, stage at presentation, extranodal involvement at
presentation). In addition, each genetic variable was analyzed
independently. Aggregate comparisons were performed using two-sample
t-test, and proportions of subsets with individual genetic
variables were compared using a two-sided Fischer's exact test.
| |
RESULTS |
Clonal chromosomal abnormalities detected by G-banding.
Clonal chromosome abnormalities were documented in 72 of the 96 cases.
Recurring gains and losses detected in the entire group are summarized
in Fig 1A. Homogeneously staining regions
(HSRs) or HSR-like marker chromosomes were noted in two tumors (218 and 806) and dmins in one other tumor (1533). Recurring translocations affecting bands 3q27, 8q24, and 18q21 were represented by 8, 3, and 13 cases, respectively (one case had translocations affecting both the
3q27 and 18q21 bands). The remaining 49 clonally abnormal cases did not
display a 14q32-associated translocation.
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| Fig 1.
Partial ideograms comparing the recurring chromosomal
gains and losses detected by G-banding in 72 of the 96 tumors assayed for gene amplification (A), the subset of 20 tumors assayed by CGH (B),
and gains and loses detected by CGH in the same subset of 20 tumors
(C). Thin vertical lines on either side of the chromosome ideogram
indicate only recurrent gains (right) or losses (left) of a chromosome
or a chromosomal region. Gains/losses were considered recurrent if
observed in two or more tumors. Thick lines in (C) indicate regions of
high copy number (amplification) as defined in the text.
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CGH analysis.
A subset of 20 specimens from the 72 with documented clonal chromosome
abnormalities were subjected to CGH analysis to identify gains and
losses of DNA in tumors with a t(14;18)(q32;q21) translocation, as well
as those without an IG gene site-associated translocation (Fig
1B and C). Seven cases (102, 251, 486, 721, 885, 956, and 1659) had the
t(14;18)(q32;q21) translocation, while the remaining 13 (23, 150, 178, 216, 248, 293, 331, 375, 970, 1368, 1533, 1593, and 1664) did not
exhibit an IG gene site-associated translocation. Comparison of
gains and losses of chromosomes and chromosomal regions detected by CGH
with those detected by G-banding showed an overall
concordance in the subset of 20 tumors with CGH detecting a higher
number of gains and losses compared with G-banding (Fig 1B and C).
Discordances may be due to previously detailed reasons.6
High-level amplification was detected at nine sites in six tumors:
1q21-23, 2p12-16, 8q24, 9q34, 12q12-14, 13q32, 16p12, 18q21-22, and
22q12 (Figs 1C and 2). Recurring sites of
amplification were noted in five tumors and comprised two cases with
amplification of 1q21-23 (248 and 1659), two cases with amplification
of 2p12-16 (150 and 248), and two cases with amplification of 8q24 (375 and 885). Among these sites, amplification of 1q21-23, 2p12-16, and 8q24 was noted in tumors with, as well as without, the
t(14;18)(q32;q21) translocation, while amplification of 12q12-14,
16p12, and 22q12 sites was noted only in tumors with the
t(14;18)(q32;q21) translocation. Of the three tumors, which showed
cytogenetic evidence of gene amplification, one with dmins (1533) was
studied by CGH and did not identify an amplified region. The G-banded
karyotype of this tumor was 46,XX, +3dmin[20] suggesting that the
amplification itself was of low level.
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| Fig 2.
Partial CGH karyotypes (left) and corresponding ratio
profiles (right) illustrating high level amplification of chromosomal regions in DLBL tumors studied. Hybridized tumor DNA was visualized via
FITC (green) and control DNA 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 eight
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 0.80 and 1.20 for loss and gain,
respectively.
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|
Southern blot analysis for copy numbers of candidate amplified genes.
Genes mapped to the chromosomal regions of amplification were
considered as candidate amplified genes if they previously had been
shown to be amplified in human tumors and/or if their cellular functions included regulation of signal transduction events. Such genes, identified by searching the Genome Database (GDB)
are listed in Table 1.6,13-35
Among these genes, we decided to determine the incidence of
amplification of two groups of genes. One comprised REL,
MYC, and BCL2 genes. These were selected because of
their previously established roles in lymphoid lineage development and deregulated expression in lymphomagenesis.3,16,17,36
REL and the related NFKB2 gene were previously shown to
be deregulated by rare IG gene site-associated
translocations,37,38 and we recently showed REL to
be frequently amplified in DLBL.6 MYC and
BCL2 are frequently deregulated by IG gene
site-associated translocations in various lymphoma
subsets,39 while anecdotal instances of amplification of
these genes have previously been reported in CGH
assays.7,20,40-42 In this study of DLBLs, four or more
copies indicative of amplification were noted in 23% of cases for
REL, 16% of cases for MYC, and 11% of cases for
BCL2 (Table 2 and
Fig 3).
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| Fig 3.
Southern blot analysis of DNA extracted from tumors (7, 150, 885, and 980) and normal placenta with MYC, REL,
BCL2, and D2S48 probes. The calculated copy numbers are listed.
Tumor 150 exhibited amplification of 2p12-16 (REL) and 18q21-22
(BCL2), and tumor 885 exhibited amplification of 8q24
(MYC) by CGH.
|
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In a subset of 78 tumors from this cohort, we previously identified 20 with REL amplification; we noted one additional tumor in this
study (Table 2). No REL rearrangements suggesting 2p13-16 translocation were encountered. None of the 14 cases, which showed 4
copies of MYC, exhibited the t(8;14)(q24;q32) translocation. Similarly, a t(14;18)(q32;q21) translocation or BCL2 gene
rearrangement was not noted in the 10 cases, which showed 4 copies of
BCL2. A BCL2 gene rearrangement was identified in 15%
of all the cases studied.
The second group of genes screened were GLI, CDK4, and
MDM2, which have previously been mapped to amplicons in band
12q13, a chromosomal region that has frequently been found to be
amplified in a variety of tumors, particularly gliomas and
sarcomas.26,27,29,30 None of the DLBLs assayed exhibited
more than 10 copies of any of the three genes (Table 2), and in seven
cases (150, 251, 252, 1404, 1584, 1593, and 1712), all three genes were
found to be in higher copy number. In two of these cases (251 and
1593), CGH indicated a gain of chromosome 12. In four other cases (311, 1319, 1602, and 1693), two of the genes were in >4 copies (311:
GLI and MDM2; 1319 and 1602: CDK4 and
MDM2; 1693: GLI and CDK4). Discontinuous amplification of genes mapped to this region, such as that exhibited in
case 311, has been reported in other tumors.29 In case 885, which showed amplification of 12q12-14 by CGH, none of the three genes
tested exhibited higher than normal copy numbers suggesting possible
amplification of other genes.
Clinical correlation analysis.
The median follow-up for survivors in the cohort was 27 months. As
expected, median survival was greater among those with limited stage
(I-II) disease (P = .08, log rank; P = .03, Breslow). A
correlation was noted between genetic alterations and stage of disease
at presentation; thus, cases presenting with stage I-III disease had a
lower frequency of BCL2 rearrangement and/or 4 copies
of REL, MYC, BCL2, GLI, CDK4,
or MDM2 compared with cases presenting with stage IV disease
(P = .03). With the exception of the cohort of cases with
REL amplification, there were no associations between the
genetic alterations and extranodal involvement, when analyzed in
aggregate or separately. Of the 21 cases with REL amplification, 18 presented with extranodal involvement, compared with
47 of 70 cases without REL amplification (P = .1),
indicating a trend towards REL amplification in extranodal
lesions. In 13 of the 18 cases with REL amplification and
extranodal involvement, the gastrointestinal system was involved.
| |
DISCUSSION |
In this study, we found a good concordance in gains and losses detected
by G-banding and CGH, although the latter analysis identified many more
changes in addition to those detected by the former. In addition,
G-banding did not identify any evidence of high copy number of
chromosomal regions detected by CGH. This higher efficiency of CGH to
detect copy number changes is not unexpected because this method scans
the DNA of the entire genome taking into account subpopulations of
tumor cells, which may not proliferate adequately in short-term
culture, to be detected in conventional cytogenetic analysis. In
addition, increased copy numbers of chromosomal regions hidden in
marker chromosomes are usually undetectable by G-banding.
Gene amplification, commonly associated with tumor progression and
clinical outcome in solid tumors, has not been widely identified in
hematopoietic tumors. Recent CGH analysis of small series of NHL
samples comprising multiple histologic subsets has identified several
sites of amplification, including 8q24 and 18q21.7,20,40-42 The only large series representing a specific histologic subgroup assayed for gene amplification was DLBL, in which REL was shown to be amplified in 23% of cases.6 To determine the
incidence and possible role of gene amplification in an at diagnosis,
histologically-defined, and clinically significant subset of NHL, we
undertook a CGH analysis, followed by identification of candidate
genes, in a cohort of DLBL.
The genetic and clinical heterogeneity of DLBL presents a biologic, as
well as a clinical challenge. The commonly recurring IG gene
site-associated translocations leading to deregulation of specific
genes occurs only in a proportion of cases, as shown in this study.
BCL6, one of the three genes deregulated by such translocations, plays an important role in the genesis of
DLBL.3 In addition, BCL6 undergoes mutations
(hypermutation) in the 5 regulatory region in more than 70% of
cases of DLBL, providing another possible mechanism for BCL6
deregulation.3 Thus, nearly all DLBLs contain deregulated
BCL6 alleles. Deregulation of BCL2, an antiapoptosis
gene, and MYC, a DNA-binding transcription factor, have been
known to be the primary events in the genesis of follicular center cell
(FCL) and Burkitt's lymphoma (BL), respectively.39 The BL
phenotype is invariably associated with MYC deregulation; its
role in the genesis of DLBL is unknown. However, MYC
deregulation has been suggested to comprise a second and contributing
genetic event in the progression of BCL2-deregulated FCL to
DLBL.43-45
The data presented here suggest that REL, MYC, and
BCL2 genes may be more frequently involved in DLBL than is
indicated by the frequency with which they are deregulated by
chromosomal rearrangement. In the tumor panel assayed, there was no
overlap between tumors with amplification and translocation affecting
REL, MYC, and BCL2, suggesting that
amplification and rearrangement are independent pathways to
deregulation or overexpression of these genes. A similar conclusion was
recently reached in a study of BCL2 overexpression in DLBLs
with rearrangement versus amplification of the gene.41 They
also indicate that the role of aberrant expression of these genes in
lymphomagenesis is more prevalent than hitherto realized based on the
incidence of cytogenetic translocations or DNA rearrangements. The
relationship between rearrangement, amplification, and expression remains to be characterized. The site of BCL6 was not seen to be amplified in the CGH analysis, which is consistent with its frequent
deregulation by translocation, as well as mutation in DLBLs.46
We also identified in this panel of at diagnosis DLBL, a higher copy
number of three genes mapped to 12q13, (GLI, CDK4, and MDM2) with approximately the same frequencies as were noted for MYC and BCL2. In addition, all three genes were found
to be in high copy number in seven cases, indicating a large amplified region. The role of amplification of these three genes or other candidate genes mapping to 12q13-14 region in lymphomagenesis remains
to be determined.
In this study, we have identified the spectrum of chromosomal sites
amplified in at diagnosis DLBL shown by CGH analysis and, using a
candidate gene approach, show frequent amplification of REL,
MYC, BCL2, GLI, CDK4, and MDM2 genes.
Whether these amplifications comprise primary events leading to
transformation or secondary events that underlie progression and
clinical outcome, remains to be determined. However, our clinical
correlation studies have indicated that BCL2 rearrangement
and/or amplification of REL, MYC, BCL2,
GLI, CDK4, and MDM2 are associated with
advanced stage disease at presentation. As noted above, MYC
deregulation has been associated with progression of
BCL2-deregulated FCL, and BCL2 overexpression itself
has been associated with adverse clinical outcome in FCL, as well as
DLBL, in some studies.36 Our previous data of a
pretreatment and posttreatment cohort of DLBL suggested that
REL amplification may be associated with extranodal
presentation.6 The results of our present study of at
diagnosis DLBL are consistent with this observation. Further candidate
gene and/or positional cloning approaches can be expected to
identify additional amplified genes mapping in the amplified
chromosomal regions identified, thereby providing new clues to the
genetic basis of progression and clinical behavior of DLBL.
| |
FOOTNOTES |
Submitted August 6, 1997;
accepted February 25, 1998.
Supported by Grant No. CA-66999 from the National Institutes of
Health/National Cancer Institute, Bethesda, MD, and the Lymphoma Foundation.
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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