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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1180-1187
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Institute of Pathology and Division of Medicine, Wuerzburg
University, Wuerzburg, Germany.
Genetic aberrations associated with the development of extranodal
high-grade large B-cell lymphoma originating in the stomach have not
been fully identified yet. We analyzed 31 such lymphomas using 73 microsatellite markers for allelic imbalance and microsatellite instability. The highest frequency (42%) of loss of heterozygosity (LOH) was found on the long arm of chromosome 6. We identified 2 LOH
hot spots on 6q21-22.1 and 6q23.3-25, flanked by markers D6S246-D6S261
and D6S310-D6S441, respectively, containing putative tumor suppressor
genes (TSGs). These 6q aberrations were found to be the sole allelic
imbalance in 1 patient only; they were mostly accompanied by additional
abnormalities. Several known TSGs, namely, the APC, p15/p16, p53, and
DCC genes, were found to suffer frequent LOH during lymphomagenesis.
LOH was also detected in regions containing putative TSGs on 7q and
13q14. Frequent amplification of genomic material was found in the 2p,
3q27 at the BCL-6 gene locus, 6p, 7q, 11q23-24 at the MLL gene locus, and 18q regions. Analysis of the pattern of occurrence of these aberrations revealed an association of the amplification of the MLL
gene region with LOH at the p53 locus (P = .02). Only low frequency of microsatellite instability (MSI) was detected in these
lymphomas and MSI incidence increased with age (P = .01). Karyotypic instability thus plays the main role in the development of
gastric high-grade large B-cell lymphoma. Common genetic aberrations responsible for lymphomagenesis are deletions of 6q, loss of p53, and
amplification of the 3q27 and the MLL gene regions.
(Blood. 2000;95:1180-1187)
Twenty-five percent to 40% of malignant non-Hodgkin's
lymphomas (NHL), the so-called primary extranodal lymphomas, arise
outside the lymph nodes, most frequently in the gastrointestinal
tract.1 Studies of gastric lymphomas, which constitute the
most common extranodal lymphoma, have suggested that their
clinicopathologic features are more closely related to the structure
and function of mucosa-associated lymphoid tissue (MALT) than of
peripheral lymph nodes.2 Recently, marginal zone B-cell
lymphoma of MALT-type was established as a distinct clinicopathologic
entity in the group of extranodal lymphomas.3 It presents
either as a low-grade indolent disease showing characteristic
aberrations like translocation t(11;18)(q21;q21)4 or a more
aggressive high-grade lymphoma.5 In contrast to their
low-grade counterparts, only few data are available regarding
cytogenetic and molecular aberrations in high-grade large B-cell
lymphomas originating in the stomach. These tumors show mostly complex
aberration patterns with several recurrent features such as frequent
deletions of chromosome 6q, or partial or whole gains of chromosomes 1, 3, 7, 11, 12, 17, 18, and 21 detected in cytogenetic and comparative
genomic hybridization (CGH) studies (unpublished data).4,6
Several frequently occurring molecular abnormalities have been studied
and well documented. Du et al7 found p53 deletions and
mutations in low- and high-grade extranodal, primarily GI tract
lymphomas, and suggested that partial inactivation of the p53 gene
might play an important role in the development of the low-grade
lymphomas, whereas complete inactivation might be associated
with high-grade transformation. It has been shown that some gastric
high-grade large B-cell lymphomas overexpress the BCL-6
protein8 or demonstrate rearrangements of the BCL-6 locus
on chromosome 3q27.9 Homozygous deletion of the p16 gene was found in 14% of patients with gastric high-grade large B-cell lymphoma.10 On the other side, some of the genetic
abnormalities occurring in nodal B-cell NHL, namely, rearrangements of
BCL-1, BCL-2, and c-myc, are absent in extranodal
lymphomas.11-14 However, all these molecular studies have
usually narrowly focused on a role of a particular individual gene such
as p53 in the pathogenesis of the disease and did not investigate the
sequence and relationship between the various gene abnormalities detected.
Genomic instability is a basic property of tumor cells. It generates
the diversity necessary for a cancer cell to escape from inherent
restraints on growth. One form of genomic instability is the result of
inactivation of TSGs, which is the hallmark of tumor suppressor pathway
of oncogenesis. The other form results from the malfunction of the DNA
mismatch repair system and leads to replication error phenotype
(RER+) characteristic of mutator pathway of
oncogenesis.15,16 The RER+ phenotype is
infrequently detected in nodal B-cell NHL,17 but recent
findings suggested that the mismatch repair system defects might play a
significant role in the pathogenesis of extranodal lymphoma.18 Both aspects of genomic instability can
be evaluated using 1 method, microsatellite analysis.
To assess the contribution of both the tumor suppressor and mutator
pathways to the extranodal gastric high-grade large B-cell lymphomagenesis, we analyzed 31 such patients with 73 microsatellite markers. We characterize the genetic aberrations common in the tested
subjects and show that abnormalities typical for the tumor suppressor
pathway play a major role in the pathogenesis of this disease.
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 (GDB). PCR primers were synthesized at MWG Biotech (Munich, Germany) and 1 oligonucleotide of each primer pair labeled with fluorescent dye phosphoramidites FAM, TAMRA, or HEX. Paired normal and tumor DNA samples from each patient were amplified with PE AmpliTaq Gold enzyme (Perkin-Elmer, Foster-City, CA) in multiplex PCR reactions using 50 ng of genomic DNA as a template, under conditions specified by GDB. Thirty cycles were carried out in a PE-2400 thermal cycler (Perkin-Elmer) 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 a 373 DNA Sequencer (ABI, Foster City, CA). The automatically collected data were analyzed with GENESCAN software as described in the manufacturer's manual. Only patients heterozygous for a given locus were regarded to be informative; homozygosity and microsatellite instability rendered the particular locus unevaluable for LOH or amplification. In heterozygous cases, 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 to other markers showing no change in the same multiplex PCR), then the ratios of the allele showing decreased or increased signal to the unchanged allele were calculated, first for control DNA, then for the tumor. Increase of the ratio by 40% in the tumor compared with the control was called amplification, decrease by 40% LOH. All aberrations were confirmed 2 times.
Comparative genomic hybridization (CGH) CGH was performed according to a standard protocol.23 Tumor DNA was labeled with biotin-16-dUTP, and normal DNA extracted from peripheral blood lymphocytes of a healthy donor was labeled with digoxigenin-11-dUTP (Boehringer, Mannheim, Germany). Equal amounts of test and reference DNA (1 µg each) were cohybridized on commercially available metaphase slides (Vysis, Downers Grove, IL). Detection of biotin- and digoxigenin-labeled probes was accomplished with fluorescein-isothiocyanate (FITC) antiavidin (Vector Laboratories, Burlingame, CA) or Cy3-conjugated antidigoxigenin (Dianova, Hamburg, Germany), respectively. The 4,6-diamidino-2-phenylindole counterstain was used for chromosome identification after antibody detection. Signals were visualized under a Zeiss Axiophot fluorescence microscope (ZEISS, Jena, Germany) and analyzed with the ISIS digital image analysis system (MetaSystems, Altlussheim, Germany). At least 15 metaphases per case were analyzed. For identification of chromosomal imbalances, ratios of 1.25 and 0.8 were used as upper and lower threshold, respectively. A high-level amplification was defined as an overrepresentation of genetic material with fluorescence ratio exceeding 2.0, or on the basis of observation of strong focal signals in the FITC fluorescence with corresponding ratio profile being diagnostic for overrepresentation.6 The final evaluation of CGH profiles was performed by visual control of the digital images to rule out artifacts.Fluorescence in situ hybridization (FISH) The interphase FISH MLL assay was established by selecting YAC DNA clone 785c6 localized to the MLL gene locus and as a control YAC 878c12 assigned to 11q21. After amplification of human sequences by Alu-PCR,24 probes were generated by nick translation with biotin-16-dUTP or digoxigenin-11-UTP (Roche Diagnostics, Mannheim, Germany). FISH was performed on cytogenetic preparations or tumor cells isolated from frozen tumor tissue according to standard protocols.25 To determine the cut-off level in normal interphase nuclei, cytogenetic preparations of 5 reactive lymph node specimens served as a negative control. At least 100, in the majority of cases 200, intact nuclei per slide were evaluated by a Zeiss Axiophot fluorescence microscope. Illustrations were generated by using the ISIS imaging system.Immunostaining for MSH2 and MLH1 Immunohistochemical staining for MSH2 (hybridoma clone FE11, Calbiochem, Germany) and MLH1 (hybridoma clone G168-15, PharMingen, Germany) was performed on pressure cooked, pretreated, formalin-fixed, paraffin-embedded tissue sections and visualized using standard immunoperoxidase technique. Normal tissue of the same patient served as a control. A case was considered positive for each antigen, when more than 80% of the tumor cells showed strong nuclear staining compared with normal cells on the same slide.
LOH on chromosome 6q is the most frequent allelic imbalance detected in gastric high-grade large B-cell lymphoma Seventy-three microsatellite markers were evaluated for loss or gain of chromosomal material (Table 1). The markers were chosen to cover loci of known and putative TSGs, or chromosomal regions shown to harbor gross chromosomal aberrations in a previous cytogenetic study, using a part of the same patient material.4 To reliably distinguish LOH from genomic amplification, multiplex PCR reactions with the marker in question and minimally 1 other marker used as an internal control were performed. The results were further confirmed by CGH in the great majority of patients (Figure 1), (unpublished data). Several loci on various chromosomes showed allelic imbalance in minimally 2 cases and are depicted in Table 2. The most frequent allelic imbalance detected by microsatellite analysis in this study was localized to chromosome 6. Altogether, 13 (42%) patients showed a deletion of a part or the whole long arm of chromosome 6. To determine more closely the extent of the deletions, we analyzed this chromosomal arm with 15 markers. Two LOH hot spots were identified (Table 3). One located in the 6q21-22.1 region (7 patients, 23% of informative cases), defined by markers D6S246 and D6S261, and the second one in the 6q23.3-25 region (10 patients, 32% of informative cases), between markers D6S310 and D6S441. Frequent allelic imbalance was also displayed on the short arm of chromosome 6 (7 patients, 4 amplifications, 2 deletions). However, 2 of the patients showing amplification of 6p had concomitant isochromosome 6p (unpublished data) and LOH with all 6q markers pointing to a loss of the whole long arm of chromosome 6. Therefore, the 6p amplification in these 2 subjects was caused by presence of isochromosome 6p and, thus, was a result of the 6q deletion, not expression of an isolated amplification of 6p.
Other regions showing consistent LOH Locus of the p53 gene on chromosome 17p13.1 assayed for with the TP53CA marker showed the second most frequent LOH (Table 2), evident in 6 patients (22% of informative cases). This frequency is similar to that reported in previous MALT lymphoma studies.7 Other tumor suppressor loci displaying consistent LOH were the APC gene locus on 5q21, showing LOH in 4 patients (14%), and the p15/p16 locus on chromosome 9p21 that displayed LOH also in 4 patients (14%). The 13q14 chromosomal band containing the loci of the retinoblastoma gene and a putative TSG called Leu5 deleted in chronic lymphocytic leukemia26 was investigated with several markers. Three patients (10%) displayed LOH, but all 3 deletions detected were rather large and comprised both the retinoblastoma and Leu5 gene loci.High-level amplification of the MLL gene region Several microsatellites on the long arm of chromosome 11 (Table 1) were used in the analysis of the 11q chromosomal arm, which is the breakpoint of the reciprocal translocation t(11;18)(q21;q21) found in low-grade MALT lymphoma. Markers positioned in the 11q23-24 region, but not a marker for the cyclin D1 gene locus on 11q13.3 showed amplification of genomic DNA in 5 cases (16%). The 11q23 region contains the MLL gene involved in recurrent translocations in leukemias and lymphomas. Because a concomitant CGH study revealed a high-level 11q23 amplification in 1 of these patients, we further performed FISH analysis with YAC 785c6 contained in the MLL gene locus on 3 patients whose material was available. One of these patients showed high-level amplification detected by FISH, CGH, and microsatellite analyses; the other 2 demonstrated 3 copies of the MLL gene (Figure 2 and raw data not shown).
Other consistent allelic imbalances A distinct patient group was formed by cases showing partial or complete amplification of chromosome 3. Five subjects (16%) displayed amplification of the 3q27 chromosomal region containing the locus of the BCL-6 gene (Figure 1), but 2 of the patients had actual amplification with all markers located on chromosome 3 and had trisomy 3 confirmed by cytogenetic and FISH analyses.27 Six (19%) patients showed allelic imbalance in the 18q chromosomal region. Three (10%) of them had LOH at the DCC microsatellite located in the DCC gene locus, but another 3 subjects showed amplification with the marker D18S474 located more centromerically. Region 12p12-13 containing the TEL gene was assayed for, with several markers showing amplification of this region in 2 cases (6% of informative cases). Five patients (16%) revealed allelic imbalance in the 2p16-21 region.Grouping of LOHs and amplifications Besides the frequency of genomic deletions and amplifications, the pattern of occurrence of these changes and their associations were studied. When the results of the analysis were plotted in a diagram (Table 4), it became obvious that the 6q LOH is an unifying characteristic feature present in 52% of patients showing any allelic imbalance. Thus, it seems that this deletion is one of the most important abnormalities characteristic of gastric high-grade large B-cell lymphoma. A much smaller group was formed by 5 subjects showing the 3q27 amplification. Only 1 of these subjects displayed both the 3q27 amplification and LOH on 6q, pointing at the possibility that these aberrations might belong to different pathogenetic pathways. However, independence of these 2 aberrations could not be reliably statistically investigated because of the small sample size. Another characteristic group was formed by 5 patients showing amplification of the 11q23-24 MLL gene region. Four of the patients had simultaneous LOH at the p53 locus, and this association between the 11q23-24 and p53 aberrations proved to be statistically highly significant (P = .02, 2 test, exact).
9p21 LOH occurred together with the 6q LOH and also as an isolated
abnormality in 2 patients, but not in the 3q27 group. LOH at the p53
gene locus was evident in both the 3q27 amplification and 6q LOH
groups, as was the case with other allelic imbalances detected in these
patients. Another interesting association was revealed by age analysis
of patients showing specific allelic imbalances, namely, amplifications
of 12p12-13 and LOH in the 13q14 region were exclusively associated
with older age (> 66 years). When the patients were stratified
according to the stage of disease at presentation, only
those displaying stage EII and beyond demonstrated the 13q14 LOH. None
of the subjects showing 4 or more microsatellite instability
(MSI) positive markers had a p53 LOH or 6q LOH. On the other
side, 3 of 4 patients who had no MSI positive repeats showed
6q LOH.
Only a minor group of gastric high-grade large B-cell lymphomas shows significantly increased MSI To assess the role of MSI in lymphomagenesis, all microsatellites were also evaluated for MSI. However, only 67 (3%) of 2263 genotypes revealed features of MSI. The majority (74%) of the novel alleles showed only 1 repeat difference to the original allele, 78% were additions, 22% deletions of 1 repeat from the original allele. All the MSI events were type II mutations (only 1 novel allele occurred per marker). When the frequency of MSI per individual patient was plotted in a diagram (Table 5), 2 groups of patients emerged. The first group was composed of patients who either showed no MSI (4 patients, 13%) or displayed a low level of MSI (25 patients, 81%). In this group, the MSI frequency showed a tendency to fit a binomial distribution with mean of about 2 MSI positive repeats and SD of 1.7. The second group consisted of only 2 patients (6%), showing 7 (10%) and 8 (11%) MSI positive markers, respectively. They were located more than 2 SDs apart from the mean of the first group and thus not included in the 95% confidence interval. However, for the increased frequency of MSI in these 2 cases to manifest a biologic process different from that one characteristic of the majority of gastric high-grade large B-cell lymphomas, the difference in MSI frequency is too small and statistically insignificant. Moreover, search for mutations at the polydeoxyadenine tract of the transforming growth factor beta type 2 receptor gene (TGF- RII), polydeoxyguanine
tracts of insulin-like growth factor II receptor (IGF2R) and BAx
genes, or the AGC repeat in the coding region of the E2F-4
gene, mutations that are characteristically associated with MSI-H
phenotype in colorectal carcinoma, did not reveal any MSI at these
repeats in any of the subjects studied. Immunostains for protein
products of the mismatch repair genes MLH1 and MSH2 showed a strong
nuclear staining comparable with surrounding normal tissue in more than 90% of the tumor cells in every patient (raw data not shown).
Increasing MSI incidence with age.
The patients were divided according to their age into 3 groups (< 60 years, 60-69 years, and 70 years and older) and comparison of MSI
incidence among the individual groups (means and SDs were 1.3 ± 0.8, 1.9 ± 1.3, and 3.8 ± 2.7 MSI event,
respectively) was then performed (Table 6).
A significant difference in the MSI incidence was found when the groups
of patients younger than 60 years of age and older than 70 years were
compared (Mann-Whitney U test, 1-tailed). With increasing age,
the MSI incidence showed a trend to rise (P = .012,
Jonckheere-Terpstra test), and the variability of the MSI incidence
increased (P = .02, F test).
Compared with nodal high-grade non-Hodgkin's lymphomas, few data are available concerning the characteristic chromosomal abnormalities, genetic, and molecular features of extranodal gastric high-grade large B-cell lymphomas. Those studies performed up to date failed to identify changes that would be specific for these neoplasms. They are in the majority aneuploid tumors showing a high degree of karyotypic instability. Those few nonrandom chromosomal deletions or amplifications identifiable in these tumors reflect loss or gain of genetic material and suggest the presence of TSGs or oncogenes whose function is altered during the process of malignant transformation. We performed a genomic search aiming to identify gene loci involved in the pathogenesis of high-grade large B-cell lymphoma originating in the stomach, and grouped these tumors according to their allelotype with 73 highly informative microsatellite markers located in the vicinity of either known or putative TSGs and oncogenes.
Submitted May 28, 1999; accepted October 5, 1999.
Supported by grants from the IZKF (B3) and the Sonderforschungsbereich 172, B13 of the Deutsche Forschungsgemeinschaft.
Reprints: Petr Starostik, Institute of Pathology, Wuerzburg University, Luitpoldkrankenhaus, Josef Schneider Strasse 2, D-97080 Wuerzburg, Germany; e-mail: peter.starostik{at}mail.uni-wuerzburg.de.
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.
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  S. M. Cohen, M. Petryk, M. Varma, P. S. Kozuch, E. D. Ames, and M. L. Grossbard Non-Hodgkin's Lymphoma of Mucosa-Associated Lymphoid Tissue Oncologist, November 1, 2006; 11(10): 1100 - 1117. [Abstract] [Full Text] [PDF]
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 J. P. Wittschieben, S. C. Reshmi, S. M. Gollin, and R. D. Wood Loss of DNA Polymerase {zeta} Causes Chromosomal Instability in Mammalian Cells Cancer Res., January 1, 2006; 66(1): 134 - 142. [Abstract] [Full Text] [PDF]
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 S. Wohrer, A. Puspok, J. Drach, M. Hejna, A. Chott, and M. Raderer Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) for treatment of early-stage gastric diffuse large B-cell lymphoma Ann. Onc., July 1, 2004; 15(7): 1086 - 1090. [Abstract] [Full Text] [PDF]
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M. Inoue, P. Starostik, A. Zettl, P. Strobel, S. Schwarz, F. Scaravilli, K. Henry, N. Willcox, H.-K. Muller-Hermelink, and A. Marx Correlating Genetic Aberrations with World Health Organization-defined Histology and Stage across the Spectrum of Thymomas Cancer Res., July 1, 2003; 63(13): 3708 - 3715. [Abstract] [Full Text] [PDF]
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D. Re, P. Starostik, N. Massoudi, A. Staratschek-Jox, V. Dries, R. K. Thomas, V. Diehl, and J. Wolf Allelic Losses on Chromosome 6q25 in Hodgkin and Reed Sternberg Cells Cancer Res., May 15, 2003; 63(10): 2606 - 2609. [Abstract] [Full Text] [PDF]
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 M. Inoue, A. Marx, A. Zettl, P. Strobel, H.-K. Muller-Hermelink, and P. Starostik Chromosome 6 Suffers Frequent and Multiple Aberrations in Thymoma Am. J. Pathol., October 1, 2002; 161(4): 1507 - 1513. [Abstract] [Full Text] [PDF]
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M. Raderer, A. Chott, J. Drach, C. Montalban, B. Dragosics, U. Jager, A. Puspok, C. Osterreicher, and C. C. Zielinski Chemotherapy for management of localised high-grade gastric B-cell lymphoma: how much is necessary? Ann. Onc., July 1, 2002; 13(7): 1094 - 1098. [Abstract] [Full Text] [PDF]
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E. D. Remstein, P. J. Kurtin, C. D. James, X.-Y. Wang, R. G. Meyer, and G. W. Dewald Mucosa-Associated Lymphoid Tissue Lymphomas with t(11;18)(q21;q21) and Mucosa-Associated Lymphoid Tissue Lymphomas with Aneuploidy Develop Along Different Pathogenetic Pathways Am. J. Pathol., July 1, 2002; 161(1): 63 - 71. [Abstract] [Full Text] [PDF]
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 P. Starostik, J. Patzner, A. Greiner, S. Schwarz, J. Kalla, G. Ott, and H. K. Muller-Hermelink Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways Blood, January 1, 2002; 99(1): 3 - 9. [Abstract] [Full Text] [PDF]
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R. Zhou, A. Zettl, P. Strobel, K. Wagner, H. K. Muller-Hermelink, S.-j. Zhang, A. Marx, and P. Starostik Thymic Epithelial Tumors Can Develop along Two Different Pathogenetic Pathways Am. J. Pathol., November 1, 2001; 159(5): 1853 - 1860. [Abstract] [Full Text] [PDF]
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P. Starostik, A. Greiner, S. Schwarz, J. Patzner, A. Schultz, and H. K. Muller-Hermelink The Role of Microsatellite Instability in Gastric Low- and High-Grade Lymphoma Development Am. J. Pathol., October 1, 2000; 157(4): 1129 - 1136. [Abstract] [Full Text] [PDF]
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A. Zettl, P. Strobel, K. Wagner, T. Katzenberger, G. Ott, A. Rosenwald, K. Peters, A. Krein, M. Semik, H.-K. Muller-Hermelink, et al. Recurrent Genetic Aberrations in Thymoma and Thymic Carcinoma Am. J. Pathol., July 1, 2000; 157(1): 257 - 266. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
