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PLENARY PAPER
From the Institute of Pathology, Würzburg
University, Germany.
Low-grade marginal zone B-cell lymphoma of mucosa-associated
lymphoid tissue (MALT) type can transform into high-grade diffuse large
B-cell lymphoma (DLBCL). Up to 60% of the MALT lymphomas contain the
recently described t(11;18). However, this translocation has
not been detected in any DLBCL so far. To elucidate the pathogenesis of
these tumors, microsatellite screening of 24 gastric MALT lymphomas was
performed and the results were compared with aberrations detected in a
previous study on gastric DLBCL. The most frequent aberration, found in
21% of the MALT lymphomas that were exclusively t(11;18)-negative cases, was amplification of the 3q26.2-27 region (harboring the locus
of the BCL6 gene). Allelic imbalances in regions 3q26.2-27, 6q23.3-25, 7q31, 11q23-24, and 18q21 were shared by both MALT lymphoma
and DLBCL. Loss of heterozygosity in regions 5q21 (APC gene
locus), 9p21 (INK4A/ARF), 13q14 (RB), and 17p13
(p53) and allelic imbalances in 2p16, 6p23, and 12p12-13
occurred exclusively in DLBCL. Only one of 10 t(11;18)-positive
MALT lymphomas showed an additional clonal abnormality. These tumors
thus display features of a clonal proliferation characterized by the
presence of the t(11;18). However, they only rarely display secondary
aberrations and do not seem to transform into DLBCL. In contrast,
t(11;18)-negative MALT lymphomas show numerous allelic imbalances Primary extranodal gastric marginal zone B-cell
lymphoma (MZBCL) of mucosa-associated lymphoid tissue (MALT) type
attracted much attention recently. The disease originates on
inflammatory background brought about by a chronic Helicobacter
pylori infection that initiates buildup of MALT in originally
lymphoid follicle-free stomach. Further development of lymphoma out of
the MALT is the result of continuous antigen-dependent growth of B
lymphocytes in the early phase that then progresses into a stage of
autonomous proliferation of a true low-grade lymphoma. That lymphoma
can and in some cases does develop into a high-grade
lymphoma.1-3 This sequence of events makes this disease an
attractive model on which the development of neoplasia out of a chronic
inflammatory disease can be studied.
As in other neoplasms, MALT lymphoma development is marked by a series
of genomic aberrations that contribute, step by step, to increasing
genomic instability (GI) and establishment of a population of
autonomously growing neoplastic cells at the end. Recently, the
translocation t(11;18)(q21;q21) was identified in a fraction of
low-grade MALT lymphoma cases, ranging from 21% to 60% of examined
tumors.4,5 API2 and MALT1,
genes affected by this translocation, have been cloned and the
breakpoints characterized.6-8 How the t(11;18) contributes
to the MALT lymphoma development and which regulatory pathways are
affected by altered expression of these 2 genes is still a subject of
investigation. Cytogenetic and fluorescence in situ hybridization
(FISH) studies documented the presence of other abnormalities in MZBCL
of MALT type as well.9 Trisomy 3 was reported with
frequency ranging from 20%10 to 85% of
tumors.11 Translocation t(1;14) was described as another characteristic abnormality, albeit much less frequently (in only 6 MALT-type lymphomas so far).12-14 A previous study
suggested microsatellite instability (MSI) to play an important
role in lymphomagenesis,15 but the high prevalence of
MSI-positive MALT lymphomas could not be confirmed by us and
others.16-19
Recently, we analyzed a group of 31 gastric diffuse large B-cell
lymphomas (DLBCLs) for loss of heterozygosity (LOH) and amplification of genomic DNA with a panel of 73 microsatellite
markers.20 Presuming that the same aberrations we saw in
the DLBCLs could occur in the low-grade MZBCL of MALT type, we
established a smaller panel containing 39 frequently affected
microsatellites with which to analyze the low-grade lymphomas. Here, we
report results of screening 24 such MALT lymphomas with this marker
panel and compare the aberrations detected with the results of the
high-grade DLBCL study.
Patients and samples
Microscopic dissection and DNA extraction
Microsatellite analysis Primer sequences for the amplification of microsatellite repeats listed in Table 1 were retrieved from Genome Database (http://gdbwww.gdb.org). PCR primers were synthesized at MWG Biotech (Munich, Germany) and one oligonucleotide of each primer pair labeled with fluorescent dye phosphoramidites FAM, TAMRA, NED, ROX, or HEX. Paired normal and tumor DNA samples from each patient were amplified with the AmpliTaq Gold DNA polymerase (ABI, Foster City, CA) in multiplex PCR reactions using 50 ng genomic DNA as template under conditions specified by the Genome Database. Thirty cycles were carried out in a PE-2400 thermal cycler (ABI) in a total volume of 20 µL. Aliquots of the PCR reactions were then mixed with size standard and formamide, denatured, and subjected to electrophoresis on an ABI 377 DNA Sequencer (ABI). The automatically collected data were analyzed using GeneScan and Genotyper software as described in the manufacturer's manual. Only patients heterozygous for a given locus were regarded to be informative; homozygosity and MSI rendered the particular locus unevaluable for LOH or amplification. In heterozygous genotypes, ratios of both alleles in normal and tumor tissues were calculated. If these ratios showed a difference of more than 20%, the locus was further evaluated for possible allelic imbalance. For determination of LOH or amplification in a locus, first the unchanged allele was identified (by comparison with other microsatellites showing no change in the same multiplex PCR), and then the ratios of the allele showing decreased or increased signal to the unchanged allele were calculated, first for control DNA and then for the tumor. Increase of the ratio by 40% in the tumor (as compared with the control) was called amplification; decrease by 40%, LOH. All aberrations were confirmed 2 times.
Fluorescence in situ hybridization for t(11;18) The interphase t(11;18) FISH assay was established by selecting yeast artificial chromosome (YAC) clones flanking the breakpoint region on 11q21.27 YAC clone 805c4 was chosen on the telomeric side; for the region centromeric to the breakpoint, YAC clones 963c8 and 966e4 were pooled to enhance signal intensity. All YAC clones were obtained from CEPH (Paris, France). After amplification of human sequences by Alu-PCR,28 probes were generated by nick translation with biotin-16-dUTP or digoxigenin-11-dUTP (Roche Diagnostics, Mannheim, Germany). FISH was performed on cytogenetic preparations or tumor cells isolated from fresh frozen tumor tissue according to standard protocols.29 In normal interphase cells, hybridization resulted in a close spatial relation of the differentially labeled YAC clones leading to 2 red/green signal pairs per cell. In tumors carrying the t(11;18), a derivative signal constellation with one signal pair and one separate red and green signal per nucleus was observed. To determine the cutoff level for normal interphase nuclei, cytogenetic preparations of 5 reactive lymph node specimens served as a negative control. At least 100 (in most cases 200) intact nuclei per slide were evaluated under a Zeiss Axiophot fluorescence microscope (Zeiss, Jena, Germany). Illustrations were generated using the ISIS imaging system (MetaSystems, Altlussheim, Germany).RT-PCR for t(11;18) All tumors were further evaluated for the presence of the API2-MALT1 fusion RNA product. Tumors from which fresh frozen tissue was available were analyzed using a test developed by Kalla et al.8 Paraffin-embedded/formalin-fixed tumors were analyzed by a reverse transcriptase (RT)-PCR approach described by Inagaki et al.30 However, to maximize the sensitivity of the latter reaction and precisely size the products, the second-round 5' primers were labeled with fluorescent dyes FAM or HEX and the products separated using the ABI 377 DNA Sequencer (ABI).
Gastric MZBCL of MALT type shows low frequency of genomic aberrations We collected 24 MALT-type MZBCLs of the stomach to be examined for signs of GI using microsatellite analysis. Thirty-nine microsatellite markers were chosen to be used in this study (Table 1); 29 of them were those markers having shown frequent allelic imbalance or MSI in a previous allelotype analysis of extranodal gastric high-grade DLBCL.20 To distinguish LOH from amplification of genomic DNA, multiplex PCRs with the analyzed marker and at least one other marker used as an internal control were performed. The overall level of GI in the low-grade MALT lymphomas was fairly low. Only 10 (42%) patients or 37 (5.9%) genotypes out of 623 informative analyses showed an allelic imbalance.Aberrations in regions 3q26.2-27, 11q23-24, and 18q21 are the most common allelic imbalances detected in MALT lymphoma Several loci on various chromosomes showed allelic imbalances (Figure 1). The most frequent amplification of genomic material occurred in the 3q26.2-27 region (Figure 2). It was detected in 5 patients (21% of informative cases). The smallest segment showing amplification was flanked by markers D3S3715 and D3S1262 and contains the locus of the BCL6 gene. Region 11q23-24, including the locus of the MLL gene, was screened for the amplification we found in DLBCL previously with just 2 markers; 2 amplifications and 2 LOHs were detected. Four patients revealed an allelic imbalance in the 18q21 region, twice an amplification and twice an LOH. The smallest amplified segment was flanked by markers D18S474 and D18S484; it does not contain the loci of the MALT1 and BCL2 genes. Another 2 cases had an LOH on the long arm of chromosome 6, region 6q23.3-25, assayed for by markers D6S310 and D6S441, a hot spot of deletions in gastric DLBCL. One of the deletions was extremely large and encompassed also the 6q21-22.1 region. There were sporadic imbalances on 7q31 and 9p21 one case of each.
MZBCL reveals a very low level of MSI Included in the microsatellite screening panel were markers that had shown a considerable degree of MSI in our previous study on high-grade DLBCL of the stomach.20 However, the level of MSI in the low-grade MALT lymphomas proved to be extremely low. We detected only 5 (0.6%) genotypes revealing MSI: 2 in case no. 11 and the remaining 3 in 3 other patients. All MSI events were type II mutations (only one novel allele occurred per marker), they did not cluster with any particular marker, all 5 affected a different microsatellite.Additional clonal aberrations associate with t(11;18)-negative status FISH and RT-PCR analyses for determination of the t(11;18) were performed on most fresh frozen tumors or all studied tumors, respectively. By RT-PCR, 10 lymphomas were positive for the t(11;18) and 9 were negative. When the patients were grouped according to their t(11;18) status, it became obvious that the cases positive for the translocation only rarely manifested any additional clonal aberration (Figure 3). In contrast, 6 (67%) of the t(11;18)-negative tumors revealed an allelic imbalance. The association of the t(11;18)-negative status with the manifestation of additional clonal aberrations proved to be statistically significant (P = .01, 2 test).
MGII in low-grade MALT lymphoma is significantly lower than in high-grade DLBCL We used the results of a previous DLBCL study20 to compare the degree of GI in extranodal gastric MZBCL of MALT type and DLBCL. These tumors were analyzed using 38 and 73 microsatellites, respectively; however, both microsatellite panels contained an identical core set of 29 repeats used for the comparison (Table 1). These 29 markers would detect all consistent aberrations in both lymphoma types. We designed a so-called microsatellite genomic instability index (MGII) to quantify the level of GI in these cases. The MGII is the percentage of microsatellites showing any clonal aberrationeither allelic imbalance or MSIout of the total number of
repeats analyzed. Using such a GI measure, we compared GI levels of the
MALT lymphomas positive or negative for the t(11;18) and the DLBCL
(Figure 4). The t(11;18)-positive MZBCL
of MALT type (10 cases) showed very low MGII, with mean of 0.7% and SD
of 1.48%. The MALT lymphomas negative for the translocation (9 cases)
displayed only a low-level GI, with an MGII mean of 9.3% and SD of
10.22%. The group showing the highest MGII (17.15% ± 11.13%) were
the high-grade DLBCL patients (31 cases). The MGII difference between
the t(11;18)-positive MALT lymphomas and the DLBCLs proved to be
statistically significant (P = .0001, Mann-Whitney U test). There was a significant trend to increased MGII
values in the t(11;18)-negative MALT lymphomas when compared with the t(11;18)-positive cases (P = .027, Mann-Whitney
U test).
Amplification in region 3q26.2-27 seems to be a crucial step in the development of t(11;18)-negative MZBCL To identify chromosomal regions whose losses or amplifications are key steps in the extranodal gastric lymphoma development, we compared the allelotypes of the low-grade gastric MZBCL of MALT type and the high-grade gastric DLBCL. Only the aforementioned core set of 29 repeats was used for the comparison (Table 1). Microsatellite analysis results for 13 chromosomal regions showing consistent aberrations were plotted in a bar diagram and the frequencies of allelic imbalance compared (Figure 5). The regions could be divided into 3 groups. The first group consisted of regions 3q26.2-27, 11q23-24, and 18q21, showing allelic imbalances at about the same frequency in both low- and high-grade lymphomas. The second group consisted of regions 6q21-22.1, 6q23.3-25, and 7q31, showing rare aberrations in the low-grade tumors and much higher frequency of abnormalities in the high-grade lymphomas. However, only LOH in the 6q23.3-25 region occurred in more than one of the low-grade tumors; the 6q21-22.1 and 7q31 aberrations were displayed by just one patient each. The third group contained aberrations occurring exclusively in the high-grade lymphomas: LOH in the 5q21 (APC gene locus), 9p21 (INK4A/ARF), 13q14 (RB), and 17p13 (p53) regions and allelic imbalances in the 2p16-21, 6p23, and 12p12-13 regions.
Several consistent cytogenetic abnormalities have been associated
with particular subtypes of non-Hodgkin lymphoma, the most notorious
example being t(14;18) found in follicular lymphoma.31 Recently, t(11:18)(q21;q21) was identified in 21% to 60% of
extranodal low-grade MZBCLs of MALT type4,5,32; it seems
to be the most frequent translocation found in this non-Hodgkin
lymphoma subtype. The identification of genes involved in this
translocation (the apoptosis inhibitor gene API2 and a novel
gene of unknown function called MALT1) suggests that the
t(11;18) may result in a survival advantage for MALT lymphoma
B-cell clones.6-8,33 However, at least 40% of the
same low-grade MALT lymphomas do not feature this translocation.
Moreover, none of the extranodal high-grade DLBCLs was found to harbor
the t(11;18) Altogether, the frequency of aberrations in the MZBCL of MALT type was much lower than in the DLBCL. Only 5.9% of the analyses or 42% of patients showed an allelic imbalance. Amplification of the 3q26.2-3q27 region, the most frequent consistent abnormality, was detected in 21% of patients. The smallest amplified segment was flanked by markers D3S3715 and D3S1262 (lying about 10 cM apart). Previously, trisomy 3 had been reported to be the most frequent abnormality in this lymphoma, with prevalence ranging from 20%10,34 up to approximately 60% of cases.35 However, it is also one of the most common numerical abnormalities described in other subtypes of non-Hodgkin lymphoma as well. The genetic mechanism by which trisomy 3 or amplification of the 3q26.2-27 region may contribute to lymphomagenesis is not known. An increased gene dosage effect resulting from higher copy numbers of gene(s) relevant to B-cell development or proliferation in general has been favored to explain the biological consequences underlying chromosomal trisomies. Several candidate genes are located in the D3S3715-D3S1262 amplicon of the 3q26.2-27 region, the most promising being the gene coding for phosphatidylinositol-3 kinase p110 catalytic subunit (PIK3CA), implicated as an oncogene in ovarian cancer,36 and the BCL6 gene that functions as a transcriptional switch controlling germinal center formation. Because a number of nodal DLBCLs derive from germinal-center B cells,37 deregulated BCL6 expression might contribute to lymphomagenesis by preventing postgerminal center differentiation.38 Indeed, some of the nodal DLBCLs and all normal germinal center B cells analyzed by complementary DNA microarrays39 showed overexpression of BCL6 and, interestingly, overexpression of PIK3CA messenger RNAs as well. Other chromosomes suffered less frequent aberrations in the low-grade
MALT lymphomas. The 11q23-24 region revealed allelic imbalance in 4 (17%) patients, 2 with amplifications and 2 with deletions.
Four cases revealed an allelic imbalance in the 18q21 region Of 19 cases in whom the results of t(11;18) RT-PCR analyses were
available, 10 revealed this translocation. When the studied patients
were grouped according to their t(11;18) status (Figure 3), the
t(11;18)-negative cases interestingly showed distinctively more clonal
aberrations as detected by microsatellite analysis. According to the
level of allelic imbalance displayed, gastric MZBCL of MALT type can be
thus divided into 2 groups: the first characterized by the t(11;18) and
rare additional clonal aberrations, the second missing the t(11;18) but
revealing significantly more other genetic aberrations
(P = .01, To identify genetic aberrations playing a role in the progression of low-grade lymphoma and early stages of high-grade lymphoma, we compared the allelotype of low-grade gastric MZBCL of MALT type that we established in this work with the allelotype of high-grade gastric DLBCL we published recently (Figure 5). Allelic imbalances in the 3q26.2-27, 11q23-24, and 18q21 regions occurred with comparable frequencies in both low- and high-grade tumors. In contrast, aberrations in regions 6q23.3-25 and 7q31 were shared by both tumor types but occurred with much higher frequency in the DLBCLs. Only LOH in the 6q23.3-25 region occurred in more than one of the low-grade tumors and thus does not appear to occur purely by chance. The last group of aberrations occurred exclusively in the DLBCLs. Among them were LOHs in the 5q21 (APC tumor suppressor gene), 9p21 (INK4A/ARF), 13q14 (RB), and 17p13 (p53) regions and allelic imbalances in the 2p16-21, 6p23, and 12p12-13 regions. Several of the just-mentioned regions harboring known tumor suppressor genes were already shown to play a role in the low- to high-grade lymphoma transition. Du et al47 concluded that partial inactivation of the p53 gene by mutation or deletion might play an important role in the development of low-grade MALT lymphoma, whereas complete inactivation seen in 29% of DLBCLs might be associated with high-grade transformation in at least some cases. Inactivation of the INK4A gene, a cyclin-dependent kinase inhibitor and negative regulator of the cell cycle, has also been described as a possibly important event in the progression from low- to high-grade lymphoma.48,49 Two of 6 high-grade DLBCL cases analyzed by Calvert et al revealed LOH in the APC gene locus.50 However, none of these abnormalities occurred at such a high frequency as the 6q aberrations reported in our DLBCL study. The results of our present analysis suggest that the 6q23.3-25 deletion occurs even before the loss of the p53, INK4A/ARF, or APC gene functions as evidenced by the LOH in regions harboring these genes. On the basis of these data, we propose the following model of MZBCL of
MALT-type development (Figure 6). There
seem to be 2 pathways of MALT lymphoma development and progression. One
group of tumors develops along the pathway determined by the
dysregulation of the API2 and MALT1 genes brought
about by the t(11;18). These tumors do not accumulate enough secondary
genetic aberrations to transform into DLBCL and remain in the stage of
MZBCL. Other MALT lymphomas characterized by the absence of the
t(11;18) and increased accumulation of various clonal genetic
aberrations, most frequently the 3q26.2-27 amplification, could be the
source of tumors that eventually do transform into high-grade DLBCL. Curiously, 2 groups of tumors could be identified among the DLBCLs we
analyzed previously; they were characterized by 3q26.2-27 and 6q
aberrations and represent 16% and 42% of tumors, respectively (with
one overlapping case only). Similarly, among the MALT lymphomas, there
were 5 tumors displaying the 3q26.2-27 aberration and 2 tumors with the
6q aberration. These data invite the hypothesis that possibly
the 3q26.2-27 DLBCL group could encompass secondary DLBCL arising by
transformation from a pre-existing MZBCL showing the same aberration.
The minority of DLBCL is secondary disease transformed from its
low-grade counterpart. However, we also detected 2 low-grade lymphomas
showing the 6q aberration. These 2 cases were morphologically low-grade
tumors but still could be evolving primary DLBCL. How far this
hypothesis is correct in describing the transformation of MZBCL into
DLBCL will need to be investigated next. It is quite possible that the
DLBCL development is not as simple and there is even more heterogeneity
in the group of lymphomas currently lumped together under the label of
MZBCL of MALT type.
The heterogeneity of genetic aberrations we found in the MZBCL has immediate clinical implications. Namely, the extranodal lymphomas of MALT type characterized by the t(11;18) are unlikely to transform into high-grade lymphomas, although they may clinically present with early dissemination or advanced tumor stages. It has been shown in 2 recent studies51,52 that these are the cases resistant to H pylori antibiotic eradication therapy. This resistance, however, does not mean that these lymphomas automatically have an aggressive course. With the spreading popularity of stomach-conserving approaches, prospective studies evaluating the prognostic significance of the t(11;18) will be of fundamental significance for the further treatment of such patients. Increased attention should be devoted to cases that are t(11;18) negative. Some of them will respond to antibiotics; a recent study has shown that even some high-grade DLBCL cases could undergo remission after eradication of H pylori.53 Patients who are negative for the t(11;18) and do not respond to Helicobacter eradication therapy should be put on a regimen of intensive surveillance. Specifically, these lymphomas could be the primary candidates for transformation into DLBCL.
Submitted December 5, 2000; accepted June 4, 2001.
Supported by grants from the Interdisziplinäres Zentrum für Klinische Forschung (B3) and Sander Stiftung (no. 94.025.3).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Petr Starostik, Institute of Pathology, Würzburg University, Luitpoldkrankenhaus, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany; e-mail: petr.starostik{at}mail.uni-wuerzburg.de.
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© 2002 by The American Society of Hematology.
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Top
Abstract
Introduction
), retention of heterozygosity; (
), not informative;
(
), no amplificate; (
), genomic DNA amplification; and (
),
LOH.
