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Regular Articles |
From the Human Genome Laboratory,*
Center for Human
Genetics, Flanders Interuniversity Institute for Biotechnology,
Leuven; and the Department of
Pathology,
University of Leuven,
Leuven, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Controversy also exists concerning the necessity to distinguish MALT type lymphoma from nodal and splenic marginal zone cell lymphoma. All three marginal zone cell lymphomas are considered to arise from a common normal counterpart, the marginal zone cell. Indeed they share similar morphological features and an identical immunophenotype. Moreover, and despite the frequent failure of cytogenetic analysis in this malignancy, a comparable cytogenetic profile of the three subtypes of marginal zone cell lymphoma has been demonstrated, with a particularly high incidence of trisomy 3 and trisomy 18.8,9 On the other hand, translocation t(11;18), one of the rarely found structural anomalies in marginal zone cell lymphomas, has been reported to occur exclusively in extranodal, low grade MALT type marginal zone cell lymphomas.10
Using two cases of gastric MALT type lymphoma documented by the t(11;18)(q21;q21) we recently succeeded in cloning the breakpoints on chromosome 11 and 18. Furthermore we demonstrated that the API2 gene, an inhibitor of apoptosis, and a novel gene on 18q21, named MLT, are rearranged in this translocation.11 Based on these data a reverse transcription-polymerase chain reaction (RT-PCR) approach was developed to detect t(11;18)(q21;q21) in a series of 58 consecutively received gastrectomy specimens demonstrating involvement by non-Hodgkin’s lymphoma to define the incidence of this particular cytogenetic anomaly in gastric lymphomas and to clarify its role in the pathogenesis of MALT type lymphoma as well as in other lymphomas affecting the stomach.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All gastrectomy specimens involved by non-Hodgkin’s lymphoma and documented by at least one representative freshly frozen tissue block were included in the study. These 58 consecutively received cases were collected in the department of pathology of the University Hospitals, Catholic University of Leuven over a period of 15 years. The series includes one case from a previous study.11 No cytogenetic data were available for the remaining cases.
In none of the cases was evidence of a lymphomatous process documented in the clinical history before the gastric complaints that led to the gastrectomy. Moreover, in most cases the neoplastic process was restricted to the stomach.
Histology was reviewed on paraffin-embedded, formalin-fixed material without knowledge of the RT-PCR findings. A minimum of two and a mean number of 10 blocks per specimen were available for the analysis. Diagnosis was based on hematoxylin and eosin (HE)-stained sections and on the results obtained using a panel of immunohistochemical stainings including pan-B cell and pan-T cell staining, IgM, IgA, IgD, kappa, and lambda staining as well as CD5, CD10, and CD23 stainings performed on paraffin and/or frozen tissue sections. The lymphoma was subtyped according the International Lymphoma Study Group proposal or REAL classification.1 MALT type lymphoma was diagnosed only in cases without clear evidence of a large cell proliferation. Gastrectomy specimens with sheets and clusters of large cells within the MALT type lymphoma, with large cells colonizing pre-existing follicle centers or with a tumor mass composed of large cells only associated with MALT type lymphoma, were recorded as MALT type lymphoma and large cell proliferation. All cases composed exclusively of large cells were recorded as de novo diffuse large B cell lymphoma. Finally, the cases presenting as Burkitt’s/Burkitt’s-like lymphoma are listed separately.
In 3 of the 58 cases, frozen mesenteric lymph node biopsies taken at the time of the gastrectomy and involved by the lymphoma were available for study.
RT-PCR Analysis of the t(11;18) Fusion Transcripts
Total RNA was extracted from no more than 10 tissue sections, 20
µm thick, using Trizol reagent (Life Technologies, Mevelbeke,
Belgium). These sections were taken from a representative frozen
tissue block stored at -80°C comprising the lymphomatous tissue as
checked on an HE-stained frozen tissue section. Four hundred
nanograms of total RNA was used as template for each RT-PCR
reaction (Titan one tube RT-PCR system, Boehringer Mannheim, Mannheim,
Germany). Primers used in the different RT-PCR experiments are
listed in Table 1
.
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PCR products were cloned in pGEM-T Easy (Promega, Madison, WI), nucleotide sequences were determined by dideoxy chain termination with fluorescein isothiocyanate-labeled primers and analyzed on an automated laser fluorescence sequencer (AP Biotech, Uppsala, Sweden).
Real Time Detection of the API2-MLT Fusion Transcript
One microgram of total RNA was converted into cDNA using Superscript Reverse Transcriptase according to the manufacturer’s recommendations (Life Technologies). The quality of the synthesized cDNA was verified by amplification of a 350 bp fragment of the GAPD gene (primers GAPD247f and GAPD596r). One microliter of the RT reaction (20 µl) was then used as template for real time detection of the API2-MLT fusion transcript using the TaqMan Universal PCR master mix and an ABI Prism 7700 sequence detector (Perkin-Elmer Corp.). For the detection of breakpoints upstream of bp 814 of MLT, primer set D was used: 15 pmol MLT-876r and 20 pmol Taqman probe MLT-845r were used in combination with 15 pmol of API2 primer A7f1 in a 50-µl reaction. For the detection of breakpoints upstream of bp 1150 of MLT, set E was used: 15 pmol MLT-1233r and 20 pmol Taqman probe MLT-1197r were used in combination with 15 pmol A7f1. Amplification conditions are 2 minutes at 94°C, followed by 40 cycles of denaturation (94°C, 20 seconds) and extension (60°C, 1 minute).
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Results |
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All lymphomas were of peripheral B cell type and could be
subdivided into four groups (Table 2)
.
The first group of 23 cases was diagnosed as marginal zone cell
lymphoma (MZCL) of extranodal MALT type. Three of these cases were also
documented by frozen blocks from involved mesenteric lymph nodes. These
biopsies showed a lymphomatous process with similar features to the
neoplasm found in the gastrectomy specimen. In most cases reactive
follicle centers surrounded by a preserved lymphocytic corona were
easily found entrapped within the neoplastic marginal zone cell
proliferation. The latter was composed of a rather monomorphic, small
to medium sized population displaying features of marginal zone cells
(centrocyte-like cells) admixed with very few, isolated large cells.
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The third group comprised 18 cases in which the lymphomatous process was composed entirely of a large B cell proliferation. No genuine MALT type lymphoma component was found, though an atrophic lymphocytic gastritis could be noted in the surrounding of the lymphoma in most of the cases. All cases included in this group were diagnosed as de novo diffuse large B cell lymphoma (DLCL) of the stomach.
The last group consisted of three cases that showed features of Burkitt’s/Burkitt’s-like lymphoma with the presence of high mitotic rate and large numbers of apoptotic cells.
Molecular Genetic Analysis
For the detection of an API2-MLT fusion transcript, nested amplification (primer set A) was performed on cDNA derived from 400 ng of total RNA extracted from the lymphoma samples after quality control of the RNA. For this control experiment a 900-bp GAPD fragment was amplified starting from the same amount of RNA in a single round of amplification (30 cycles). To identify genuine API2-MLT fusion transcripts, Southern blots containing the reaction products were hybridized with internal API2 and MLT oligonucleotide probes. For both genes these probes are located in the same exon as the primers used for nested PCR.
Fragments hybridizing with both the API2 and MLT
oligonucleotide probes were detected in biopsies of 11 of 58 patients
analyzed (Table 2)
. In one additional case an aspecific product was
amplified as it hybridized exclusively with the API2 probe
but not with the MLT oligonucleotide. This was confirmed by
sequencing showing the presence of genomic sequences flanking exon 7 of
API2 in the aberrant RT-PCR product.
In almost half of the positive cases (5/11), a PCR fragment of
approximately 1.2 kb was observed accompanied by one or two smaller,
less intense bands (Figure 1A)
. All bands
hybridized with the internal oligonucleotide probes for API2
and MLT, respectively. Sequence analysis of these different
amplification products revealed a fusion of exon 7 of API2
to respectively bp 814, 993, or 1123 of MLT (according to
accession number AF130356). A fourth, even shorter transcript was
present among the cloned amplification products that fused exon 7 of
API2 to bp 1387 of MLT, a fragment not detected
by Southern hybridization. All fusions except that to bp 993 of
MLT generate in-frame API2-MLT
transcripts. The latter induces a switch in reading frame resulting in
a TAA stop in the MLT sequence 52 bp beyond the junction.
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. The
results on the mesenteric lymph nodes available for two positive cases
were identical to the result obtained on the corresponding gastric
sample. Clustering of the breakpoints in intron 7 of API2 indicates either the vulnerability of this region for recombination or merely the portion of the API2 protein required in the fusion protein to exert its function. RT-PCR analysis with primers in exon 7 of API2 and a MLT primer at its stop codon (set C) did not identify additional cases, suggesting also an essential contribution of MLT to the fusion protein.
Next we assessed the feasibility of the RT-PCR approach on an ABI Prism
7700 sequence detector. All cases demonstrating the
API2-MLT fusion had their breakpoint in intron 7
of API2. The fraction of the MLT gene fused to
exon 7 of API2 varied, however. Therefore, two separate
RT-PCR reactions had to be optimized to keep the amplicon length below
300 to 400 bp, a prerequisite to retain maximum sensitivity. As the
API2 sequence turned out to be unsuitable, TaqMan probes
were derived for the MLT sequence included in the fusion
product. Primer set D aimed at the detection of breakpoints upstream of
bp 814 of MLT, the other (E) upstream of bp 1150 (Materials
and Methods, Figure 1C
). First-strand cDNA was synthesized from all 58
RNA samples, and their quality was verified by amplifying a 350-bp
fragment of the GAPD gene. Then both
API2-MLT reactions were performed on the 58 cDNA
samples. As a measure of the accumulation of an amplification product
the threshold value (CT) was used. The
CT value indicates the cycle at which a
statistically significant increase in emission intensity of the
reporter dye of the probe can be observed in the cDNA sample
versus the negative control. Only the 11 cases demonstrating
an API2-MLT fusion with the initial RT-PCR
approach showed accumulation of a PCR product by real time detection.
The six cases with breakpoints upstream of bp 1123/1150 of
MLT showed only amplification with primer set E. The other
five cases with their breakpoint upstream of bp 814 gave signals with
both primer sets. The CT values of 23 to 25
obtained with set D were consistently lower than those of 30 to 32
obtained with set E (Figure 2)
, which
could be explained by the larger size of the generated amplicon (601 bp
with set E vs. 244 bp with set D). Gel
electrophoresis of the amplification products obtained with set E,
however, showed a single amplification product of approximately 300 bp
(results not shown). This corresponds to the shortest, alternatively
spliced product observed in our initial experiments that will have a
length of 292 bp with set E. Its lower level of expression explains the
higher CT values observed when compared to set D.
The six cases with a breakpoint upstream of bp 1123 or 1150 showed
amplification with primer set E, and their CT
values were around 25.
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All 11 positive cases were diagnosed as extranodal MALT type lymphoma without large cell component. These cases did not significantly differ, regarding clinical characteristics and morphological and phenotypic features, from the MALT type lymphomas without large cell component, lacking the translocation. In addition, no correlation was found between the molecular findings and the H. pylori status.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study we detected t(11;18)(q21;q21) by RT-PCR in 11 cases studying a series of 58 consecutive gastrectomy specimens diagnosed as primary non-Hodgkin’s lymphoma of the stomach. The developed RT-PCR approach aimed at the detection of API2-MLT fusion transcripts beyond exon 3 of the API2 gene.14 This exon was originally chosen because it contains the ATG start codon and two and a half of the three baculovirus IAP repeat domains with the anti-apoptotic properties of the protein. A second round of nested amplification was routinely performed to amplify the signal from those RNA samples of marginal quality, as observed after GAPD control amplification, and/or with a limited portion of tumor mass in the specimen. Southern hybridizations with internal API2 and MLT oligonucleotides proved that all but one of the amplified fragments represented genuine API2-MLT fusions.
The breakpoints on chromosome 18 were scattered throughout the MLT gene. In half of the positive cases (5/11), exon 7 of API2 is fused with bp 814 of MLT. However one or two smaller, less intense bands could always be observed and sequence analysis revealed an even shorter fourth one. Sequence analysis of genomic clones demonstrated 3' splice consensus sequences flanking the MLT sequence at positions 814, 993, 1123, and 1387, respectively (Baens M, Steyls A, Dierlamm J, De Wolf-Peeters C, Marynen P, manuscript submitted). Therefore, the genomic breakpoints in these cases are most likely located in the intron preceding an MLT exon starting at bp 814 and alternative splicing generates variable API2-MLT transcripts. Fusions between exon 7 of API2 and bp 1123 or bp 1150 of MLT were observed four and two times respectively, whereas an API2-MLT fusion identical to that of case 2 from our previous report11 was not detected in this study. For all fusions it was confirmed that the MLT sequences attached to exon 7 of API2 represent proper exons (Baens et al., submitted).
Clustering of the API2 breakpoints permitted us to set up a RT-PCR approach on an ABI Prism 7700 sequence detector. Two different reactions were optimized that allow identification of fusions between exon 7 of API2 and bp 541/814 or bp 1123/1150 of MLT respectively. All cases diagnosed with an API2-MLT fusion by the original RT-PCR approach were also positive after 40 rounds of real time detection. The increased sensitivity of the real time amplification detection technique allowed us to skip the second round of nested amplification.
The API2-MLT fusion transcript, detected in 11 gastrectomy specimens by conventional RT-PCR and by real time PCR, occurred only in cases diagnosed as MALT type lymphoma, included in group I. None of these cases harbored a significant large cell proliferation defined as follicular colonization, sheets of blast cells or a large cell tumor mass. The incidence of the t(11;18) in low grade MALT type lymphoma reaches 48% in our study, an incidence that supports a close association of this chromosomal anomaly with this particular subtype of marginal zone cell lymphoma and therefore suggests a role for the API2-MLT transcript in the histogenesis of this lymphoma.
Like Ott et al,10 we did not find any t(11;18) positive samples among DLCL, the Burkitt’s/Burkitt’s-like lymphomas and MALT type lymphomas comprising a large cell proliferation, so quoted high grade component. MZCL including low grade MALT lymphomas are composed predominantly of small to medium sized cells responsible for the characteristic picture at low power and only a few larger, stimulated cells can be found admixed. The mechanisms involved in the occurrence of a clear-cut large cell component within this lymphoma, generally indicated as high grade MALT lymphoma, remain enigmatic. Data provided by immunohistochemical stainings and molecular analysis support investigators considering the presence of a large cell component within MALT type lymphoma as a transformation and/or progression from a low grade lymphoma into a high grade disease. Both techniques revealed the same light chain restriction and/or the same IgH rearrangements in the two components of the lymphomatous process as performed in a limited number of cases.15 Based on these results it was even postulated that the vast majority, if not all, lymphomas of the stomach should be considered as extranodal MALT type lymphomas. From that point of view gastric neoplasms composed only of large cells merely represent transformed small cell malignancies of which the pre-existing lymphoma is no longer detectable due to overgrowth by the transformed population.5 The exclusive occurrence of t(11;18) by RT-PCR in low grade MALT type lymphoma points toward the distinct character of the extranodal MZCL of MALT type occurring in the gut. As far a large cell component occurring in this lymphoma is indeed related to the MALT type lymphoma15,16 or merely represents a composite lymphoma comprising a diffuse large B cell lymphoma and a MALT type lymphoma as suggested by others17 is still problematic. Nevertheless, our data fully support a clear distinction of MALT type lymphoma from diffuse large B cell lymphoma of the stomach.
We previously demonstrated that the t(11;18) was accompanied by a cryptic deletion of the 3' part of the API2 gene, which precludes the expression of the reciprocal MLT-API2 transcript and attributes the oncogenic properties to the API2-MLT fusion protein.11 RT-PCR analysis of the reciprocal MLT-API2 transcript demonstrated expression in no more than 3 cases documented with the t(11;18), including case 2 from our previous study.11 This observation further strengthens the importance of the API2-MLT fusion protein, although we cannot exclude that in rare cases variant breakpoints might occur, eg, within the 3' UTR of MLT. Recent studies showed that a construct containing only the baculovirus IAP repeat domains of API2 is sufficient for inhibition of caspases and suppression of apoptosis.18 However, the present study supports a specific role for the MLT portion in the fusion protein as in all cases either an in-frame fusion with MLT is created, or alternative splicing occurs generating both in-frame and out-of-frame products. In the latter case the functional in-frame fusion products are clearly the more abundant.
In conclusion, we present a RT-PCR technique to detect t(11;18) in a minimal amount of RNA material obtained from frozen tissue sections. The translocation was found in almost half of the cases diagnosed as MALT type lymphoma on a gastrectomy specimen. Consequently, application of this technique on endoscopic biopsies will provide a new and very instructive additional diagnostic tool to distinguish between reactive lymphoid infiltrates and MALT type lymphoma in patients affected by H. pylori infection.
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Acknowledgements |
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Footnotes |
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Supported by a grant from the Belgian Cancer Association (to C. De W.-P.) and by grants G.0153.96 and G0377.97 from the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen of Belgium (to P. M.). M. B. is a Postdoctoraal Onderzoeker and P. M. is an Onderzoeksdirecteur of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Belgium.
Accepted for publication January 6, 2000.
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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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 Y. Hara, N. Nakamura, T. Kuze, Y. Hashimoto, Y. Sasaki, A. Shirakawa, M. Furuta, K. Yago, K. Kato, and M. Abe Immunoglobulin Heavy Chain Gene Analysis of Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma Invest. Ophthalmol. Vis. Sci., October 1, 2001; 42(11): 2450 - 2457. [Abstract] [Full Text] [PDF]
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H. Liu, H. Ye, A. Dogan, R. Ranaldi, R. A. Hamoudi, I. Bearzi, P. G. Isaacson, and M.-Q. Du T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10 Blood, August 15, 2001; 98(4): 1182 - 1187. [Abstract] [Full Text] [PDF]
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H. Inagaki, M. Okabe, M. Seto, S. Nakamura, R. Ueda, and T. Eimoto API2-MALT1 Fusion Transcripts Involved in Mucosa-Associated Lymphoid Tissue Lymphoma : Multiplex RT-PCR Detection Using Formalin-Fixed Paraffin-Embedded Specimens Am. J. Pathol., February 1,&nb |
VDJ4-like sequence. Large arrows depict
the position of the different MLT breakpoints, smaller
ones the alternative splice sites used when a breakpoint upstream of bp
814 occurs. Numbering is according to MLT accession
number 