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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4321-4330
Characteristic Pattern of Chromosomal Gains and Losses in Primary
Large B-Cell Lymphomas of the Gastrointestinal Tract
By
Thomas F.E. Barth,
Hartmut Döhner,
Claudius A. Werner,
Stephan Stilgenbauer,
Magdalena Schlotter,
Michael Pawlita,
Peter Lichter,
Peter Möller, and
Martin Bentz
From Medizinische Klinik und Poliklinik V, Universität
Heidelberg, Heidelberg; Pathologisches Institut der Universität
Ulm, Ulm; and Deutsches Krebsforschungszentrum, Heidelberg, Germany.
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ABSTRACT |
In contrast to low-grade B-cell lymphomas originating in the
gastrointestinal (GI) tract, only few cytogenetic data are available for the large cell, highly malignant variants. We studied 31 large B-cell lymphomas of the GI tract by comparative genomic hybridization (CGH) and fluorescence in situ hybridization using specific DNA probes
(FISH). The most frequent aberrations were gains of all or of parts of
chromosomes 11 (11 cases), 12 (9 cases), 1q (4 cases), and 3q (4 cases). Losses of parts of chromosome 6q and of parts of the short arm
of chromosome 17 (6 cases each) were found most frequently. In four
cases a total of seven high-level DNA amplifications was detected. In
two of these cases, involvement of specific protooncogenes (REL
and MYC) was shown. Some genetic aberrations seemed to be
associated with an inferior clinical course: patients with
 2 aberrations had a significantly shorter median
survival. Furthermore, all patients with gains of all or parts of
chromosome arm 1q and with high-level DNA amplifications as well as
seven of nine patients with gains of all or parts of chromosome 12 died
of lymphoma. In conclusion, the pattern of chromosomal gains and losses
in large B-cell lymphomas was different from data reported for
low-grade (MALT) lymphomas of the stomach and bowel, especially with
respect to the high incidence of partial gains of chromosome arm 11q
and of all or parts of chromosome 12 and the low frequency of polysomy
3. In addition, our data suggest that chromosomal gains and losses
detected by CGH and FISH may predict for the outcome of patients with
this tumor entity.
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INTRODUCTION |
THE MAJORITY OF primary extranodal
lymphomas arise in the gastrointestinal (GI) tract. Recently, low-grade
lymphoma of the mucosa-associated tissue (MALT) has attracted a lot of
attention, and major advances have been made in the understanding of
pathogenetic mechanisms as well as in the development of new treatment
strategies.1-3 For these low-grade lymphomas, several
cytogenetic studies have revealed characteristic chromosomal
aberrations. Trisomy 3, which is rarely found in nodal non-Hodgkin's
lymphomas (NHL), has been described in about 60% of low-grade GI
lymphomas using interphase cytogenetics.4 In marginal zone
B-cell lymphomas, which by morphology and by immunophenotype are
regarded to be closely related to MALT lymphomas, trisomy 3 has been
found with approximately the same incidence by banding
techniques.5 In addition, in low-grade B-cell GI NHL the
translocation t(11;18)(q21;q21.1) and trisomies of chromosomes 7, 12, and 18 as well as structural aberrations of chromosome 1p have been
identified by banding techniques.6-9
In contrast, only few data are available regarding cytogenetic
aberrations in large B-cell GI lymphomas (ie, high-grade lymphomas of
the GI tract). In two small series complex karyotypes with multiple
structural and numerical aberrations were found by G-banding analysis
(ref 10, four cases; ref 7, one case). In addition, Du et
al11 have described a high incidence of p53 deletions or mutations in primary extranodal high-grade lymphomas, most of which
originated in the GI tract. To obtain a comprehensive view of
chromosomal gains and losses, we analyzed samples of 31 primary large
B-cell lymphomas of the GI tract by fluorescence in situ hybridization
using specific DNA probes (FISH) and by comparative genomic
hybridization (CGH).12 For FISH studies a DNA probe set
allowing the detection of frequent genomic alterations in nodal B-cell
lymphomas was used.13 For 30 of the 31 cases, clinical data
were available and were correlated with the molecular cytogenetic data.
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MATERIALS AND METHODS |
Lymphoma classification.
Freshly frozen tumor samples of 31 consecutive patients (14 male, 17 female; age 23 to 89 years; median 71 years) with primary large B-cell
lymphomas of the GI tract were analyzed (24 gastric lymphomas, 4 lymphomas of the small intestine, and 3 lymphomas of the ileocoecal
region). Examination of routine histology (hematoxylin and eosin
[H&E], Giemsa, periodic acid-Schiff [PAS]-stainings) together with CD20-positivity of the tumor cells lead to the
classification of these 31 lymphomas as highly malignant B-cell
lymphomas with large cell cytology. Subclassification was carried out
according to the revised European-American classification of lymphoid
neoplasms (REAL-classification).14 The series
did not contain cases of Burkitt's or Burkitt-like lymphomas or
immunodeficiency-associated large B-cell lymphoma. The majority of
tumor samples did not contain any detectable small- or medium-sized
(low-grade) component. Seven tumors (marked by an asterisk in
Table 1) were secondary large cell
lymphomas on the background of marginal zone B-cell lymphoma (of
MALT-type). Not all lymphomas were entirely "diffuse"; a few also
featured some nodular pattern of growth. Therefore, the tumors were
collectively referred to as "large B-cell lymphomas originating in
the GI tract."
Microscopic dissection of tumor tissue.
To assure a high tumor cell content in the analyzed sample, which is an
important prerequisite for CGH studies, in each case 30 serial 10-µm
sections from frozen tumor blocks were obtained. For the reliable
identification of tumor areas, every fifth section was stained with
H&E. To avoid artefacts caused by fixation and staining, only the
nonstained serial sections were used for microdissection. In these
sections, areas containing high percentages of tumor cells were
identified by comparison with the adjacent stained sections. Such areas
of interest were marked and dissected under microscopic control. In the
first six cases of our series, sections were stained after
microdissection to assess the efficiency of this approach. In each of
these cases, the dissected area was still surrounded by lymphoma
tissue, indicating the high purity of the selected material.
Comparative genomic hybridization.
Genomic DNA was prepared from fresh tumor tissue as
described15 using proteinase K digestion and
phenol-chloroform extraction. CGH was performed as previously
reported.16 Briefly, tumor DNA was labeled with
biotin-16-dUTP (Boehringer Mannheim, Mannheim, Germany) and normal
human control DNA was labeled with digoxigenin-11-dUTP (Boehringer
Mannheim) by a standard nick-translation reaction. One microgram of
biotin-labeled tumor DNA, 1 µg of digoxigenin-labeled control DNA,
and 70 µg of human Cot-1-DNA (BRL Life Sciences, Gaithersburg, MD)
were cohybridized to slides with metaphase cells from blood of a
healthy donor. After hybridization for 1 to 2 days and
posthybridization washes, control and test DNAs were detected via
rhodamine and fluorescein isothiocyanate (FITC), respectively. For
identification, chromosomes were counterstained with DAPI
(4,6-diamidino-2-phenylindole).
Digital image analysis.
Image analysis was performed using an epifluorescence microscope
(Axioplan; Zeiss, Jena, Germany) and the commercially available image
analysis systems CYTOVISION (Applied Imaging, Sunderland, UK) or ISIS
(MetaSystems, Altlu heim, Germany). For each case, at least 15 metaphase cells were evaluated. Ratio values of 1.25 and 0.75, which
have been proven to provide robust criteria for diagnosing
overrepresentation and underrepresentation,17,18 were used
as upper and lower thresholds for the identification of chromosomal
imbalances. Overrepresentations were considered as high-level
amplifications when the fluorescence ratio values exceeded 2.0 or when
the FITC fluorescence showed strong focal signals and the corresponding
ratio profile was diagnostic for overrepresentation. The extension of
imbalanced regions was assessed by the comparison of the fluorescence
ratio profiles with the corresponding regions in chromosome ideograms.
Assignment of highly amplified sequences to chromosomal bands was
performed by comparison of signal intensities and DAPI banding on
individual chromosomes.
FISH.
For interphase cytogenetic analysis, six probes detecting imbalanced
aberrations and probe sets for the diagnosis of the t(11;14)(q13;q32) and the t(14;18)(q32;q21) were used. The probes screening for imbalanced aberrations mapped to chromosomal regions frequently altered
in nodal B-NHL and were as follows: YAC clones 866e7 mapping to 3q26
and 963d6 mapping to 6q21 (both obtained from the CEPH YAC library);
YAC clone 755b11 mapping to 11q22.3-23.119,20; "cos
p16" consisting of a pool of eight overlapping cosmid clones covering approximately 250 kb of the CDKN2 gene on
9p2121; "cos p53" containing four overlapping cosmid
clones mapping to 17p13 spanning the p53 tumor-suppressor
gene22; and probe "c13S25"consisting of two
cosmid clones (ICRFc108I155 and ICRFc108L2145) mapping to the D13S25
locus on 13q14.23 In addition, in one case (no. 16) the
cosmid probe cos-myc 7224 containing sequences of the
MYC protooncogene was used. For analysis of the
t(14;18)(q32;q21), the following probes were used: a YAC clone
containing the BCL2 gene (yA153A6) on chromosome 18; for chromosome 14 a pool of cosmid clones cos-C 1/2,
recognizing the C1 and C2 gene segments
proximal to the JH-region,24 and of YAC clone
Y6, identifying VH-segments telomeric to the JH-breakpoints in the IgH gene25 was used. For
the detection of the t(11;14)(q13;q32) the same probes were used for
chromosome 14; for chromosome 11 the differentially labeled 540-kb YAC
clone 55g7 spanning the region between the major translocation cluster and the CCND1 gene in the BCL1 locus at 11q13 was
applied.20 Hybridization was performed as described
previously to nuclei isolated from frozen tissue samples.26
In each experiment, two probes coupled to different reporter groups
were hybridized simultaneously and served as mutual internal controls.
Preparations were only evaluated for a specific DNA probe, if the
respective internal control exhibited two hybridization signals in more
than 90% of interphase cells. Thus, a high hybridization efficiency
was assured. Experiments were evaluated using an epifluorescence
microscope (Axioplan; Zeiss) connected to a charged coupled device
(CCD) camera. In each case, at least 200 cells were enumerated.
Southern blot analysis.
Southern blot analysis was performed as described.15
Briefly, 8 µg of genomic DNA was digested with EcoRI,
separated by agarose gel electrophoresis, and transferred to nylon
membranes (Boehringer Mannheim). A 777-bp REL-specific probe
representing exon 6b was generated by polymerase chain reaction
amplification using c-DNA clone Rc/CMV-c-Rel27,28 as
template C (kindly provided by P.A. Baeuerle and M.L. Schmitz,
Freiburg, Germany). The probe was labeled by random priming using
32PdCTP. For control hybridizations, the genomic fragment
gMHC-1-D, 4.2 kb in length, from the cardiac -myosin heavy-chain
gene, MYH7, located on 14q12-q13 was used.29 The degree of
REL amplification was determined by densitometric evaluation of
the autoradiograph with hybridization signals from probe and control
DNAs.
Twenty-one of the 31 cases were analyzed for the presence of the
Epstein-Barr virus (EBV) genome. These included 10 of 11 cases with
overrepresentations of sequences on 11q. Ten micrograms of cleaved
cellular DNA was separated by agarose gel electrophoresis and
transferred onto a nylon filter. Hybridization was performed in 50%
formamide, 2× sodium chloride/sodium citrate (SSC)
buffer at 42°C using the
32P-labeled 3.07-kb EBV-Bgl II U fragment as probe.
This probe detected the internal repeat I sequence in the EBV genome
with a sensitivity better than 0.1 EBV DNA copies per cell.
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RESULTS |
Comparative genomic hybridization.
In 21 of the 31 cases, chromosomal imbalances were identified by CGH
analysis. Gains of chromosomal material were more frequent than losses
(42 gains v 14 losses). The most frequent aberrations were
overrepresentations of all or parts of chromosomes 12 (9 cases) and 11 (6 cases) of the long arm of chromosome 1, of parts of chromosome 2 (4 cases each), and of chromosomes 8 and 9 (3 cases each). Gains of parts
of chromosomes 5 and 16 were detected in 2 cases each, while a partial
gain of chromosome 3 was detected in only one case. The most frequent
deletions involved the long arm of chromosome 6 (5 cases) and the long
arms of chromosomes 2 and 13 (2 cases each). The gains and losses
identified by CGH are summarized in Fig 1.
Partial ratio profiles of the cases with gains mapping to chromosome 11 are shown in Fig 2.
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| Fig 1.
Summary of chromosomal imbalances detected by CGH in 31 patients with large B-cell lymphomas of the GI tract. Lines on the left
indicate loss of chromosomal material, lines on the right refer to
gains of chromosomal material. Squares represent high-level DNA
amplifications. Gray lines indicate cases, in which the ratio profiles
showed a clear shift toward underrepresentation or overrepresentation; however, the diagnostic thresholds were not reached. In these patients
aberrations were confirmed by interphase cytogenetic analysis. The
numbers on top of each line refer to the patient analyzed.
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| Fig 2.
Average ratio profiles of chromosomes 11 in cases with
overrepresentations of sequences. The percentages below the case
numbers indicate the size of the subclone with gain of 11q as
determined by interphase cytogenetics. The arrow indicates the
chromosomal map position of YAC clone 755b11, which was used for
interphase analysis. For cases 2, 6, 10, 12, 13, and 22, images were
acquired and evaluated using the Cytovision software package (Applied
Imaging). Cases 5, 7, and 27 were evaluated using the ISIS software
package (MetaSystems). The ratios of FITC to rhodamine fluorescence are plotted along the chromosomes. The central line (asterisks) indicates a
ratio value of 1.0; the lines to the right indicate ratio values of
1.25 (all cases) and 1.5 (all cases except nos. 5 and 7), respectively; and the lines on the left indicate values of 0.75 (all cases) and 0.5 (all cases except nos. 5, 7, and 27), respectively. In case nos. 7 and
27, adequate material was limited and therefore only CGH analysis was
performed. #In these cases, the diagnostic thresholds were not reached.
However, there is a clear shift of the ratio profiles toward
overrepresentation. In these cases, gains of 11q were diagnosed by FISH
analysis. For cases 16 and 25, in which gains were diagnosed only in
minor subclones, no shifts of the ratio profiles were observed.
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In 4 of the 31 patients, a total of 7 high-level DNA amplifications
were identified in the tumor samples. These were mapped to the
following chromosomal regions: 5p15, 5q33-34 and 9q32-33 (no. 6); 12p12
and 16q23-24 (no. 12); 2p13-15 (no. 14); and 8q24 (no. 16). Partial CGH
karyotypes of all chromosomes carrying high-level DNA amplifications
are shown in Fig 3.
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| Fig 3.
Partial CGH karyotypes of cases with high-level DNA
amplifications. Images were acquired and evaluated using the CYTOVISION software package (Applied Imaging). Numbers at the bottom indicate the
respective chromosomes. Hybridization with the tumor DNA is shown as
gray level images. The band-like hybridization signals (arrows)
indicate highly amplified chromosomal sequences. On the right side of
the ideograms, the average ratios of FITC/rhodamine fluorescence are
plotted ("ratio profiles"). The central line indicates a ratio
value of 1.0; lines to the right indicate ratio values of 1.25 and 1.5, respectively; and lines to the left indicate ratio values of 0.75 and
0.5. n = number of chromosomes analyzed for calculating the
respective average ratio profile.
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Identification of amplified genes.
In case 14, a high-level DNA amplification mapping to chromosomal bands
2p13-14 was identified. This is the chromosomal localization of the
REL proto-oncogene. Southern blot hybridization showed a
sevenfold amplification of this gene (see Fig 4C).
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| Fig 4.
(A) Photomicrograph of a dual-color hybridization
obtained with YAC clone 755b11 mapping to 11q22.3-11q23.1 (detected via FITC, green) and YAC clone 866e7 mapping to 3q26 (detected via rhodamine, red) to cells of patient no. 6. In three cells, three or
four green hybridization signals are seen indicating an
overrepresentation of sequences on band 11q22.3-11q23.1 in these cells.
In contrast, only two red hybridization signals are present indicating
a normal copy number of sequences on band 3q26. (B) Photomicrograph of a dual-color FISH experiment with cosmid probe cos-myc 72, containing sequences of the MYC proto-oncogene detected via rhodamine
(red) and the YAC clone 963d6 mapping to band 6q21 detected via FITC (green). In this case (no. 16), CGH analysis showed a strong bandlike hybridization signal at chromosomal band 8q23-24.3. In three of the
cells a tight cluster of red hybridization signals is visible indicating an amplification of these sequences. In contrast, two green
signals are seen in all cells. (C) Southern blot analysis of DNA of
case no. 14 (right) and DNA from a placenta (left) serving as an
internal control. Probes for the REL proto-oncogene and MYH7 (control) are marked on the right side. Note the high
intensity of the REL signal in this case. Densitometric
evaluation showed a sevenfold amplification of this gene.
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In case 16, a strong bandlike signal was observed on chromosomal bands
8q23-24.3. This is the region where the MYC proto-oncogene is
localized. FISH analysis using an MYC-specific probe showed a
tight cluster of signals indicating the presence of an amplification of
this gene. In contrast, simultaneous hybridization with the probe
YAC963d6 resulted in two distinct hybridization signals in more than
90% of cells (see Fig 4B).
Interphase cytogenetics.
To define the cut-off levels for the various DNA probes, hybridization
experiments to cells obtained from frozen samples of normal tonsillar
tissue (n = 5) were performed. By analogy to previous interphase
studies (see eg, ref 30), the cut-off levels were defined by the mean + 3 SD of the respective results in the experiments with the five
tonsils. Thus, a deletion was diagnosed whenever the percentage of
cells exhibiting  1 hybridization signal exceeded the mean + 3 SD of
the percentage of cells exhibiting 1 hybridization in the control
experiments. For the various probes, the cut-off values for diagnosing
a deletion are given in parentheses: YAC 963d6 (3.4%); p16 (9.75%);
D13S25 (9.6%); p53 (12.4%). Overrepresentations were diagnosed if
cells exhibited 3 hybridization signals in percentages exceeding the
respective cut-off values: YAC 866e7 (8%); p16 (6.6%); YAC 755b11
(3.1%); D13S25 (12.6%). A t(11;14) was diagnosed if more than 3.5%
of interphase cells exhibited two chromosome 11, three chromosome 14 signals, and one cohybridization of a chromosome 11 and a chromosome 14 signal (mean + 3 SD of the respective result in the experiments with
the five tonsils). A t(14;18) was diagnosed if more than 4.5% of
interphase cells exhibited two chromosome 18 signals, three chromosome
14 signals, and one cohybridization of a chromosome 18 and a chromosome
14 signal.
In 29 of the 31 large B-cell lymphomas, sufficient material for
interphase cytogenetics was available. For detection of the t(11;14)
and the t(14;18), a subset of 18 cases was investigated. The most
frequent aberration was a gain of sequences on the long arm of
chromosome 11, which was detected in 9 of 29 cases (percentage of cells
with 3 hybridization signals: 13% to 85%; median 41%). In 6 of 29 cases, a deletion of the p53 tumor-suppressor gene was identified
(13.5% to 80% of cells; median 30%). Only 4 of 29 cases exhibited a
gain of sequences on the long arm of chromosome 3 (12%, 26%, 13.5%,
and 75% of cells, respectively). In three cases, a gain of sequences
on the short arm of chromosome 9 was detected (16%, 29%, and 78% of
cells). In an additional case (no. 4) a hyperploidy was diagnosed. In
regions with normal genomic content based on the CGH profiles (ie, 6q21
and 3q26), interphase analysis showed more than two hybridization
signals in the majority of cells (see Table
2). By contrast, interphase cytogenetic analysis using the "cos
p16" probe resulted in two hybridization signals in more than 60%
of nuclei, demonstrating the presence of a p16 deletion in this case.
Deletions within chromosomal band 13q14 were identified in four cases
(89%, 21%, two cases 13.5%). One case exhibited a gain on chromosome
band 13q14. On chromosomal band 6q21 four cases showed only one
hybridization signal in high percentages of cells (92%, 67.5%, 65%,
and 46.5%).
Both the t(11;14) and the t(14;18) were detected in only 1 of 18 cases
each (nos. 28 and 13, respectively). The percentages of
cells harboring the translocation were below 10%. In
Fig 4, representative examples of FISH
experiments are shown. The data of the interphase analyses are listed
in Table 2.
Comparison of FISH and CGH.
In 11 instances, aberrations were detected both by FISH and CGH. In 20 instances, gains or losses were identified by interphase analyses;
however, the respective CGH profiles were not in the diagnostic range.
In the majority of these cases (n = 13) this was caused by the presence
of aberrations in subclones of the analyzed samples. In other cases,
the size of the imbalanced segments most likely was below the spatial
resolution of CGH (see Fig 2). For a reliable detection, gains or
losses of at least 10 Mbp are required (see refs 31 and 32). In 44 instances, aberrations identified by CGH were mapped to chromosomal
regions, for which no DNA probes were used in our series. These data
support a combined approach exploiting the advantages of both CGH
(comprehensive screening of the genome) and FISH (detection of small
aberrations, even in subclones of the tumor).
EBV status.
Of the 21 cases studied, only 1 case (no. 1) showed the presence of EBV
sequences by Southern blot analysis.
Correlation of molecular cytogenetic data with the clinical course.
Of 30 patients, 17 are still alive and in complete remission 1 to 91 months (median, 47 months) after diagnosis. One patient (no. 31) was lost during follow-up. The remaining 13 patients died from
lymphoma 0.5 to 101 months (median, 4 months) after diagnosis. The
patients with less complex molecular cytogenetic karyotypes (0 or 1 aberration, n = 15) had a significantly higher probability of survival
than patients with two or more aberrations (median survival 48 months
v 13 months; P = .022, Wilcoxon test). Furthermore,
although the patient number is limited, there seemed to be a
correlation between specific genetic findings and prognosis. Seven of
nine patients with gains of all or part of chromosome 12 died 0.5 to 25 months (median, 3 months) after diagnosis. Similarly, the four patients
carrying a gain of the long arm of chromosome 1 and four patients with
high-level DNA amplifications died from lymphoma 0.5 to 12 months
(median, 0.5 months) and 0.5 to 23 months (median, 0.5 months) after
diagnosis, respectively. Survival data for the most frequent genetic
aberrations are listed in Table 3.
| |
DISCUSSION |
Because of the limited availability of fresh tumor tissue for
chromosomal banding analyses, only few cytogenetic data of large B-cell
lymphomas originating in the GI tract have been reported. In this
study, different molecular cytogenetic techniques were used to achieve
a comprehensive analysis of genetic aberrations in these lymphomas.
Comparative genomic hybridization was combined with interphase
cytogenetic analysis using a set of DNA probes allowing the detection
of frequent chromosomal anomalies in B-cell neoplasias. With this
approach, aberrations were detected in 26 of the 31 tumors.
The most frequent alteration in our study was a gain of material on
chromosome 11 identified in 11 of the 31 cases. Based on the CGH data,
the smallest commonly overrepresented region spanned chromosomal bands
11q22-q23. In this region, proto-oncogenes are located, for which a
possible pathogenetic role in hematological malignancies has been
demonstrated (eg MLL/ALL1,33,34
RCK,35 LPC,36
BOB1,37 and PLZF38). Gains of
chromosome 11 have been described rarely in nodal lymphomas of patients
without immunosuppression or in low-grade gastrointestinal lymphomas.
In contrast, it is frequent in secondary lymphomas occurring in
immunocompromised hosts, such as organ transplant recipients or human
immunodeficiency virus-infected subjects.39 Virtually all
of these secondary lymphomas are associated with EBV infection, and
frequently involvement of the GI has been observed.40 In
our series, the EBV genome was identified in tumor cells of only 1 of
21 patients. This finding is in line with the clinical data: none of
the patients had any evidence of an underlying disorder causing
immunosuppression. Thus, a direct link between EBV infection and GI
lymphomas with specific aberrations on 11q was not substantiated, and
this aberration may be a characteristic feature of large B-cell
lymphomas of the GI tract.
In contrast to low-grade MALT lymphomas including GI lymphomas, in
which trisomy 3 was found in more than 50% of cases,4,7 we
identified gains of this chromosome only in 4 of our 31 cases with
large B-cell lymphomas: gains of parts of chromosome 3 were found in 2 of 7 tumors with low-grade component and only 2 of 24 cases without
low-grade component. Thus, aberrations involving chromosome 3 may be
less important in putatively primary high-grade GI lymphomas. This is
in support of a previously published interphase cytogenetic study using
a chromosome 3-specific repetitive DNA probe. In this series, trisomy
3 was less frequent in high-grade than in low-grade MALT
lymphomas.11
In addition to a comprehensive study of chromosomal imbalances, a
subset of our series (n = 18) was also investigated for the presence of
the t(11;14) and the t(14;18), which are among the most common balanced
aberrations in NHL. These aberrations were found in only one case each.
Percentages of cells carrying the respective aberration were low
(<10%), and in both cases other aberrations were present in higher
percentages of cells. These findings indicate that neither the t(11;14)
nor the t(14;18) are among the primary genetic events in large B-cell
lymphoma of the GI tract. A similarly low incidence of the t(14;18) has
been reported before.7,41
In four cases, a total of seven high-level DNA amplifications were
identified. All of these cases had multiple molecular cytogenetic aberrations. The incidence of such DNA amplifications was similar to
other lymphomas.42-45 Several of the amplified regions
coincide with the chromosomal localizations of proto-oncogenes, which
may be of pathogenetic relevance in the respective cases. Using a candidate gene approach, in two instances the involvement of such proto-oncogenes could be demonstrated: in one case with a high-level DNA amplification mapping to chromosomal bands 2p13-15, an
amplification of the REL proto-oncogene was shown using
Southern blot hybridization. Such REL amplifications have been
described before in extranodal lymphomas.43,46 In another
case with a high-level DNA amplification mapping to chromosomal band
8q24, amplification of the MYC proto-oncogene was shown. This
gene is known to be rearranged much more frequently in GI lymphomas
than in nodal lymphomas.47 However, MYC
amplification has not been described in GI lymphomas before.
Despite the limited number of patients, some molecular cytogenetic
findings seemed to be associated with the clinical outcome. One
important factor was the complexity of the genetic alterations. Patients with two or more aberrations had a significantly shorter median survival (13 months) than patients with one aberration or a
normal molecular cytogenetic karyotype (48 months). In addition, all
five patients, in whom no chromosomal rearrangements were found, had a
favorable clinical course with long-lasting complete remissions. These
data are in line with results from two large studies investigating
various types of nodal NHL.48,49 Furthermore, some specific
chromosomal imbalances, ie, gains on 1q and on chromosome 12, and the
presence of high-level DNA amplifications were associated with a
particularly unfavorable course of disease.
All patients with gains of all or parts of 1q and/or high-level
DNA amplifications as well as 7 of 9 patients with gains of all or
parts of chromosome 12 died of lymphoma (median survival: 7 months for
1q, 3 months for high-level DNA amplifications, and 3 months for gains
on chromosome 12). In a large study of nodal diffuse large cell NHL,
aberrations on 1q have been shown to be associated with poor
prognosis.48 With respect to gains on the long arm of
chromosome 12, no prognostic impact has been described in high-grade
B-cell NHL. For chromosome arm 12q, in our series the commonly
overrepresented region extended from bands 12q24.1 to 12q24.3. This is
the chromosomal localization of a recently described gene,
BCL7A, which has been demonstrated to be of pathogenetic relevance in a Burkitt lymphoma cell line.50 In a previous
study based on nine cases of NHL the presence of homogeneously staining regions, the banding hallmark of gene amplifications, was associated with poorer prognosis.51
In conclusion, the combined molecular cytogenetic approach resulted in
a comprehensive analysis of chromosomal gains and losses in large
B-cell lymphomas of the GI tract. The pattern of aberrations was
different from low-grade (MALT) lymphomas of the stomach and bowel,
especially with respect to the high incidence of partial gains of
chromosome 11q and of all or parts of chromosome 12 and the low
frequency of polysomy 3. In addition, our data suggest that the
gains and losses detected by CGH and FISH may predict for the outcome
of these lymphomas.
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FOOTNOTES |
Submitted June 30, 1997;
accepted January 23, 1998.
Supported by the Deutsche Forschungsgemeinschaft (Grant No. Be
1454/5-1) and the Tumorzentrum Heidelberg/Mannheim.
Address reprint requests to Martin Bentz, MD, Medizinische
Klinik und Poliklinik V, Hospitalstr.3, 69115 Heidelberg, Germany.
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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ACKNOWLEDGMENT |
We gratefully acknowledge Profs Christian Herfarth, Michael
Wannenmacher, and Armin Quentmaier (all of Heidelberg, Germany), as
well as Drs Werner Schaupp (Weinheim, Germany) and Rolf Sippel (Mosbach, Germany) for providing clinical data of some of the patients.
We thank Dr Richard Schlenk (Heidelberg, Germany) for support in the
analysis of our clinical data and Sabine Gantner for skillful technical
assistance.
| |
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G. Ott, J. Kalla, A. Steinhoff, A. Rosenwald, T. Katzenberger, U. Roblick, M. M. Ott, and H. K. Muller-Hermelink
Trisomy 3 Is Not a Common Feature in Malignant Lymphomas of Mucosa-Associated Lymphoid Tissue Type
Am. J. Pathol.,
September 1, 1998;
153(3):
689 - 694.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
Abstract