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Regular Article |
From the Departments of Pathology*
and
Medicine,§
Nagoya City University Medical
School, Nagoya; the Laboratory of
Chemotherapy,
Aichi Cancer Center Research
Institute, Nagoya; and the Department of Pathology and Clinical
Laboratories,
Aichi Cancer Center Hospital,
Nagoya, Japan
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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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t(11;18)(q21;q21) has been identified as a recurring cytogenetic
abnormality in MZBLs, particularly in those of MALT
type.9-13
Because balanced translocations are thought to
play a pathogenetic role in the development of B-cell lineage lymphomas
such as Burkitt’s lymphoma,14
follicular
lymphoma,15
and mantle cell lymphoma,16,17
the presence of t(11;18)(q21;q21) may provide some clues to the
pathogenesis of extranodal MZBLs. Recently, we and others showed that
the c-IAP2/HIAP1/MIHC/API2 gene on chromosome 11 and a novel
gene, MLT/MALT1, on chromosome 18 were fused as a result of
this specific translocation.18,19
These studies showed the
presence of chimeric API2-MALT1 transcripts, consisting of
the N-terminal region of the API2 gene and the C-terminal
region of the MALT1 gene, in cases with
t(11;18)(q21;q21). After the discovery of the
API2-MALT1 fusion in MZBLs of MALT type, 
100 MALT
lymphomas were examined for this novel fusion, and one-third of the
cases were found to be positive.18-22
This recurrent
detection of the API2-MALT1 fusion suggested that MALT
lymphoma is in fact neoplastic.
API2 was first identified as a molecule interacting with TRAF1 and
TRAF2 and involved in the signal transduction of the anti-apoptotic
pathway mediated by tumor necrosis factor receptor II.23
API2 contains three baculovirus repeat inhibitor of
apoptosis (IAP) domains, one caspase recruitment domain
(BIR) (CARD), and one RING finger domain.24
The
common domain of the inhibitor of the apoptosis family is the BIR
motif, which has been shown to fulfill an essential anti-apoptotic
function.25
Although the function of the protein encoded
by MALT1 gene remains unknown, it shows homologies with the
immunoglobulin-like domain of CD22{beta}, the laminin-5 
3b subunit, and
F22D3.6 of Caenorhabditis elegans.19
Our
previously published data suggest that truncation of the
API2 gene distal to its three BIR domains and fusion of this
truncated gene with the carboxy-terminal region of MALT1 may
lead to an increased inhibition of apoptosis and thereby help MALT
lymphomas to survive.20
The detection of chimeric API2-MALT1 transcripts is important for exploration of the pathogenesis of MALT lymphoma as well as of clinicopathological significance because it represents direct evidence of the clonal expansion of lymphoma cells and may be relevant for prognosis. So far, reverse transcriptase-polymerase chain reaction (RT-PCR) has been the major tool for the detection of API2-MALT1 fusion transcript;20-22 because there are at least four breakpoints in each API2 and MALT1 genes, the detection of this fusion transcript requires high quality RNA so that frozen tumor materials are mandatory. Because the advantages of being able to use routinely prepared paraffin samples far outweigh any demerits, we were interested in developing a detection assay that can be used for archival specimens. Here we describe our efforts to establish a multiplex RT-PCR assay to detect various API2-MALT1 fusion transcripts using archival formalin-fixed, paraffin-embedded lymphoma tissues.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous analyses of API2-MALT1 fusion transcripts in
MALT-type lymphomas18-22
have detected four breakpoints
in API2 at 1,203 bp, 1,446 bp, 1,701 bp, and 1,743 bp
(accession no. L49432), that were designated in this study as A1203,
A1446, A1701, and A1743, respectively (Figure 1)
. Four breakpoints have been identified
for MALT1 at 541 bp, 814 bp, 1,123 bp, and 1,150 bp
(accession no. AF130356), and they were similarly designated as M541,
M814, M1123, and M1150, respectively (Figure 1)
. The
API2-MALT1 fusion transcripts are more important for the
pathogenesis of MALT lymphoma than the reciprocal transcript,
MALT1-API2, because the 5' region of the MALT1
gene is frequently deleted.19,20
Although 16 different
fusion variants of the API2-MALT1 fusion may theoretically
be present, eight variants have been reported to date: A1446-M814,
A1446-M1123, A1446-M1150, A1701-M1123, A1203-M814, A1446-M541,
A1743-M814, and A1743-M1123.18-22
We have recently
reported on the first four variants, which were confirmed by sequencing
of RT-PCR products generated from frozen tumor materials [reported as
cases 7, 8, 2, and 3, respectively, by Motegi et al20
; the
latter two cases were cytogenetically positive for
t(11;18)(q21;q21)20
]. For the study presented
here, we used, for positive controls, formalin-fixed, paraffin-embedded
tumor sections containing these four fusion variants (A1446-M814,
A1446-M1123, A1446-M1150, and A1701-M1123).
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, an API2-side
fragment of an objective chimeric API2-MALT1 gene was PCR
amplified by using a sense primer (P1, 20 mer) and an antisense primer
(P2, 40 mer) containing both API2 (20 mer) and
MALT1 (20 mer) sequences. Similarly, a MALT1 side
fragment of the chimeric cDNA was amplified by using a sense primer
(P3, 40 mer) containing both 20-mer API2 and 20-mer
MALT1 sequences and an antisense primer (P4, 20 mer). The
API2-side and MALT1-side PCR products were
diluted to 1:1,000, then admixed at a ratio of 1:1, and subjected to
PCR using P1 sense and P4 antisense primers. The objective chimeric PCR
product thus produced was subcloned into a pGEM-T Easy Vector (Promega,
Madison, WI). After confirmation of the sequence and direction of the
chimeric PCR product, the vector DNA was treated with the
SalI restriction enzyme, followed by in vitro
synthesis of the objective transcript with the aid of the T7 RNA
polymerase (RNA Transcription Kit; Stratagene, La Jolla, CA) according
to the manufacturer’s recommendations. The transcript was treated with
RNase-free DNase I (Roche Diagnostics, Tokyo, Japan) for 3 hours, then
extracted in phenol/chloroform and resuspended in RNase-free water. The
quantity of the transcript was estimated by means of electrophoresis
and a spectrophotometer (Ultrospec III; Pharmacia Biotech, Uppsala,
Sweden). Subsequently, the transcript was diluted to 1 ng/µl in
RNase-free water. After this strategy, four variant fusion transcripts
were synthesized and then used as positive controls. The P1-P4 primer
pair (Figure 2)
used to generate transcripts, A1203-M814, A1446-M541,
A1743-M814, and A1743-M1123 were PA1-PM4, PA3-PM2, PA5-PM4, and
PA5-PM6, respectively (Figure 1
and Table 1
).
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Various negative controls were included to confirm the specificity of the RT-PCR assay. A negative control without a sample RNA was included in every experiment. Also included were a negative control without reverse transcriptase and one treated with DNase-free RNase A (Roche Diagnostics). RNA extracted from paraffin sections of nonspecific chronic lymphadenitis and chronic gastritis was also used.
Clinical Samples
Extranodal non-Hodgkin’s lymphomas were selected from the files of the Department of Pathology, Nagoya City University Medical School, Nagoya, Japan. All cases were carefully reviewed, and diagnoses were made according to the criteria of the REAL classification.2 Briefly, extranodal low-grade MZBLs of MALT type (n = 16) were composed of small- to medium-sized tumor cells with a characteristic diffuse and/or marginal zone-based infiltration pattern and the formation of lymphoepithelial lesions. Four cases were of pulmonary origin, nine cases originated in the stomach, and three cases in the colon. The immunophenotype of the tumor cells was CD20+, CD79a+, cyclin D1-, CD5-, CD10-, CD3-, CD45RO-, and CD56-. Twenty-four extranodal high-grade B-cell lymphomas (gastric origin, 17; ileum, 4; and colon, 3) contained sheets of blasts with a cytological spectrum ranging from centroblasts to immunoblasts and plasmablasts. Four of the 17 high-grade gastric cases simultaneously exhibited a low-grade component. Monoclonality was detected in all of the low- and high-grade cases by molecular and/or immunophenotypic techniques as previously described.26 Twenty-four specimens were obtained by biopsy and 16 by surgical resection.
Multiplex RT-PCR Strategy
To detect various types of API2-MALT1 fusion transcripts and to achieve maximal sensitivity, we designed a multiplex one-tube RT-PCR (the first round) followed by three parallel multiplex nested PCRs (the second round). The primers were designed so that various fusion types could be distinguished by the size of the second round PCR products. To verify the results, positive PCR products of the second round amplification were directly sequenced. Primers were designed to allow identical conditions for all RT-PCR and PCR reactions. We tested the constructed primer pairs in amplifying reactions before and after combining the different primer sets into the multiplex PCR reaction. If they did not function properly, the primers were redesigned. To minimize the risk of cross-contamination and product carry-over, strict precautions were taken including the use of filter tips, different locations in the laboratory, and indigenous pipettes for sample processing, RNA extraction, RNA amplification, and electrophoresis. All samples were tested in at least two separate experiments.
RNA Extraction from Paraffin Sections
The lymphoma samples had been fixed in 10% formalin, embedded in paraffin, and stored at room temperature for 0.5 to 15 years. Total RNA was extracted from the paraffin sections as previously described.27 Briefly, the tumor sections (3-µm thick) were deparaffinized and air-dried. With a serial hematoxylin and eosin section as a guide, lymphoma cells were scraped off with a knife and collected in a tube, then incubated at 56°C overnight in 200 µl of digestion buffer (20 mmol/L Tris, pH 8.0, 20 mmol/L ethylenediaminetetraacetic acid, 2% sodium dodecyl sulfate, and 400 µg/ml proteinase K). Total RNA was extracted with the aid of concentrated phenol/guanidine isothiocyanate (Trizol LS; Life Technologies, Tokyo, Japan), followed by RNase-free DNase I (Roche Diagnostics) treatment, and final resuspension in 50 µl of RNase-free water.
Multiplex One-Tube RT-PCR (First Round)
Five µl of RNA extracted from the paraffin sections and positive
RNA controls synthesized in vitro were heated to 70°C and
then placed on ice. The RT-PCR mixture was then added, and the final
mixture of 25 µl/tube contained 8.25 U of RNase inhibitor (Toyobo,
Osaka, Japan), 50 U of Moloney murine leukemia virus reverse
transcriptase (Life Technologies), 20 pmol/L of each primer, 200
µmol/L of each of the four deoxynucleotides, 1 U of TaqGOLD DNA
polymerase (Applied Biosystems, Foster City CA), 1x Taq
buffer containing 1.5 mmol/L MgC12, and template
RNA. Three different primer pairs (PA1-PM2, PA3-PM4, and PA5-PM6 for
the API2-MALT1 fusion transcripts) were added to the reaction mixture.
The locations and sequences of the primers are shown in Figure 1
and
Table 1
. The thermocycler was programmed first to incubate the samples
for 30 minutes at 37°C for the initial RT step, and next for 10
minutes at 95°C for inactivation of the reverse transcriptase as well
as for activation of the DNA polymerase, and then to carry out 35
cycles of PCR at 95°C for 30 seconds, at 50°C for 30 seconds, and
at 72°C for 45 seconds.
Multiplex Nested PCR (Second Round)
The first round RT-PCR product diluted with water to 1:1,000 was
subjected to three parallel second-round multiplex nested PCRs using
TaqGOLD DNA polymerase and 1.5 mmol/L MgC12. To
detect fusion genes possessing an API2 breakpoint at bp
1,203, primers PA2, PM1, PM3, and PM5 were included in the second-round
multiplex PCR (second PCR-A). Similarly, to detect fusion genes
possessing an API2 breakpoints at bp 1,446 and bp 1,701 or
bp 1,743, the second round PCR used two primer sets, ie, PA4, PM1, PM3,
and PM5 (second PCR-B) for bp 1,446 and PA6, PM1, PM3, and PM5 (second
PCR-C) for bp 1,701 or 1743. The amplification conditions consisted of
35 cycles at 95°C for 15 seconds, at 55°C for 30 seconds, and at
72°C for 45 seconds. The primers used for the second round PCR were
designed so that more than 12-bp size difference among the PCR products
was generated in each second round PCR (Table 2
, second PCR-A, -B, and -C). The PCR
products were detected by ethidium bromide staining on 8%
polyacrylamide gels. The band sizes of the fusion variants are listed
in Table 2
.
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The breakpoints of the fusion transcripts were confirmed by direct sequencing. Fragments obtained in the second round PCR were separated by electrophoresis on a low melting point gel and purified. The fragments were directly sequenced by means of cycle sequencing with dye-labeled terminators (BigDye Terminators, Applied Biosystems) and analyzed on a DNA sequencer (Model 310, Applied Biosystems). API2 primers required for the second round PCR were used as sequencing primers.
Internal Positive Control
Because false-negative results because of varying RNA quality
and/or handling errors are an inherent problem in RT-PCR assays, we
amplified the ubiquitously expressed {beta}-actin mRNA as an internal
positive control. {beta}-actin transcript amplified in the first-round
one-tube RT-PCR by using an outer primer pair, AC1 and AC2, was further
amplified in the nested PCR by using an internal primer pair, AC3 and
AC4 (Table 1)
. The size of the amplified {beta}-actin fragment was 190 bp.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four breakpoints each in API2 and MALT1
cDNA, and eight API2-MALT1 fusion variants have been
reported.18-22
As positive controls, we prepared all
eight fusion variants either from clinical samples or by artificial
generation with in vitro transcription. As shown in Figure 3
, all eight fusion variants were
successfully detected in our assay consisting of multiplex one-tube
RT-PCR (first round) and the subsequent three parallel multiplex nested
PCRs (second round, second PCR-A, -B, and -C, respectively). Because
the primers were designed to generate more than 12-bp size difference
among the PCR products in each second round PCR, fusion types could be
determined with ease by the size of the amplified products run on 8%
polyacrylamide gels (Figure 3, A–C)
. Amplified fragments in the second
round PCR were directly sequenced, and the sequence data were identical
with the fusion variants determined by electrophoresis. Nonspecific
bands were rarely observed throughout the experiments. {beta}-actin
transcript was amplified in all four clinical samples used as positive
controls. Negative controls (no template inclusion, no reverse
transcriptase inclusion, pretreatment with RNase A, and lymphadenitis
and gastritis samples) produced no visible bands.
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Clinical Samples
{beta}-actin transcript used as an internal control was amplified in
35 of 40 cases (88%); four gastric and one ileal specimens were
negative for {beta}-actin transcript. RNA preservation was not associated
with the size, length of storage, or sampling method (biopsy or
resection) of the paraffin-embedded specimens. Subsequently, 15 MALT
lymphomas and 20 extranodal high-grade B-cell lymphomas were considered
to be suitable for detection of API2-MALT1 fusion
transcripts. The clinicopathological features of these 35 cases are
shown in Table 3
. Of the MALT lymphomas,
five cases (33%) were positive for API2-MALT1 fusion
(Figure 4)
: three of four in the lung
(fusion types A1203-M814, A1446-M541, and A1446-M1150), one of eight in
the stomach (A1446-M541), and one of three in the colon (A1446-M541).
The case harboring the A1446-M1150 fusion showed a 351-bp band in the
second PCR-A (Figure 4A
, case 2) in addition to an 80-bp band in the
second PCR-B (Figure 4B
, case 2) as was also observed for the
corresponding positive control. The sequencing analyses confirmed the
results. All chimeric transcripts detected were fused in-frame, and
none of the positive cases showed atypical transcripts such as an
insertion or a deletion. No chimeric transcript was detected in any of
20 extranodal high-grade lymphomas including four cases with a
concomitant low-grade component.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Different fusion products generated by cytologically identical chromosomal translocation can have major clinical correlates. In hematological malignancies possessing BCR-ABL rearrangement, the position of the breakpoint within the BCR gene determines which BCR exons are included in the encoded chimeric tyrosine kinase, thereby leading to either chronic myeloid leukemia or acute lymphoblastic leukemia.31 In some malignant soft tissue tumors, the type of fusion created by different breakpoints has been shown to be prognostically relevant.32-34 Therefore, determination of API2 and MALT1 breakpoints by means of RT-PCR, which might be difficult when fluorescent in situ hybridization or immunohistochemistry is used, may have clinicopathological significance. RT-PCR is also useful for monitoring the minimal residual disease, particularly in MALT lymphomas, where histological identification of individual lymphoma cells in the heterogeneous cell populations of the lesions is difficult. The use of paraffin sections as the RNA source facilitates a direct comparison of the tumor histopathology with the relevant molecular data.
It is generally thought that RNA is easily destroyed by ubiquitous RNase and may be degraded during the course of tissue processing and storage of specimens. RNA samples extracted from archival specimens are rarely used for study purposes. Nevertheless, under the right conditions, RNA can be preserved for years in archival specimens, as evidenced by the successful RT-PCR results in our study, with some tumor specimens having been stored for more than 10 years. {beta}-actin transcript is a good internal control for RNA quality assessment of not only frozen but also cytological and histological materials.27 In our archival lymphoma specimens, {beta}-actin transcripts were well preserved in paraffin-embedded specimens (35 of 40, 88%), regardless of their size, storage period, or sampling method (biopsy or resection). This suggests that a fragment of small biopsy, even after it is routinely processed, could be used for our assay.
In our study, the API2-MALT1 fusion was detected only in MZBLs of MALT type, and in none of the primary high-grade or secondary high-grade lymphomas. A similar observation has been repeatedly reported in recent studies.18-22,35 MALT lymphomas harboring the API2-MALT1 fusion do not seem to show a greater likelihood of transforming to large cell lymphomas. However, genetic evidence for a clonal link between low- and high-grade components has been reported for a limited number of gastric MALT lymphomas.36 Therefore, MALT lymphomas without the API2-MALT1 translocation are expected to become the subject of future investigations.
Using RNA extracted from archival samples, we were able to identify five new cases harboring the API2-MALT1 fusion transcripts out of 15 MALT lymphomas without high-grade components. This incidence (33%) is comparable with those (21 to 48%) so far reported for frozen materials.20-22 With respect to the primary site of MALT lymphomas, API2-MALT1 fusion was positive in three of four cases of pulmonary origin, but it was detected in one of eight cases of gastric origin. As we previously pointed out,20 the lung seems to be the preferential anatomical site of origin for MALT lymphomas containing the API2-MALT1 fusion. Remstein and colleagues22 recently reported that six of 11 (55%) pulmonary MALT lymphomas were positive for API2-MALT1 fusion. Varying frequencies of API2-MALT1 fusion in gastric MALT lymphomas have been reported by different researchers, ranging from 7 to 48% of cases.20-22 Rosenwald and colleagues,35 using fluorescent in situ hybridization, detected the t(11;18) translocation in seven of 21 (33%) gastric MALT lymphomas. The reason for this variation is not clear, but we speculate that H. pylori infection in the stomach may be an important factor because the infection rate varies among the geographic regions investigated.37,38 A large-scale study will be needed to clarify the prevalence of API2-MALT1 fusion cases in various anatomical sites in relation to underlying chronic inflammation.
To summarize, we have established a multiplex RT-PCR assay for the detection of API2-MALT1 fusion transcripts using formalin-fixed, paraffin-embedded materials. The rate of detection with this assay of the API2-MALT1 gene alteration in MALT lymphomas was 33%, and this percentage is comparable with the results obtained with previously reported RT-PCR assays using frozen materials. Our multiplex RT-PCR assay can be expected to become an important tool not only for diagnosis of MALT lymphoma but also for facilitating further investigation of the clinicopathological significance of API-MALT1 fusion.
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Footnotes |
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Accepted for publication October 18, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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