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From the Laboratorio di Ematologia Sperimentale e Genetica
Molecolare,*
Servizio di Ematologia, Milano; the
Servizio di Anatomia Patologica,
Università degli Studi di Milano, Ospedale Maggiore IRCCS,
Milano; and the Istituto di Genetica,
Università di Bari, Bari, Italy
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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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The t(11;14)(q13;q32) chromosomal translocation is associated with approximately 70 to 90% of mantle cell lymphomas (MCL)15-18 and leads to an overexpression of the cyclin D1 gene.19-22 The 11q13 breakpoints in MCL are prevalently clustered in a 1-kb region, known as the major translocation cluster of the BCL-1 locus, which is located approximately 120 kb centromeric of the cyclin D1 gene. Evidence of this translocation has been reported in almost 30% of the MM cases with cytogenetically detectable 14q+:2,3 however, rearrangements of the BCL-1/cyclin D1 regions involved in MCL are rarely detected in MM by Southern blotting.8,9,23 The molecular analysis of 11q13 breakpoints in a limited number of MMs (mostly cell lines) with the t(11;14) indicates that they are highly scattered over a relatively large area encompassing the BCL-1/cyclin D1 loci, but the fact that cyclin D1 was found to be overexpressed in these cases strongly suggests that it is deregulated in MM as a result of the translocation.8,9,22,24
The detection of the t(11;14) in MM patients must be considered an important step for the evaluation of its prognostic significance, but conventional cytogenetics and Southern blotting are inadequate for this purpose. We and others have recently attempted to provide fluorescence in situ hybridization (FISH) assays for detecting this genetic lesion in MM,7,9 as has been done in MCL,17,18 but its functional consequences, particularly the deregulation of cyclin D1, have not yet been investigated in panels of MM tumors with reliable information concerning the translocation.25-27
The aim of this study was to evaluate a series of primary MMs for structural evidence of BCL-1/cyclin D1 locus involvement by means of FISH, and for cyclin D1 deregulation by means of immunohistochemistry (IHC). Our data indicate that cyclin D1 overexpression occurs in about 25% of cases and closely correlates with the presence of the t(11;14).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty-eight cases of multiple myeloma (MM) were selected from 63
patients admitted to the Hematology Service, Ospedale Maggiore IRCCS,
Milan, between 1996 and 1999. The selection was based exclusively on
the availability of a bone biopsy. The diagnosis of MM was made
according to the criteria described by Durie and Salmon.28
Bone marrow aspirates and biopsies were taken from each patient at the
same time and underwent conventional light microscopy examination and
immunophenotyping analysis. The clinical and pathological data of the
cases are summarized in Table 1
: 40 were
primary tumors at diagnosis (83.3%) and 8 were relapses (16.7%); 22
were males (45.8%) and 26 females (54.2%); median age was 65 (range,
36–85). The monoclonal component was IgG in 26 cases (54.2%), IgA in
16 cases (33.3%), and IgD in one case (2.1%); four cases were 
light chain myelomas (8.3%) and one was IgA/IgG (2.1%). The 
/
chain ratio was 28/19; one case expressed both the light chains. The
Durie and Salmon stage28
and Bartl’s histological grade
and stage29
are given only for the 40 patients at
diagnosis: 23 patients were in clinical stage I (57.5%), six in stage
II (15%) and 11 in stage III (27.5%); 22 patients had clinical
symptoms (55%). According to Bartl et al,29
29 (72.5%)
were of low-grade malignancy, nine (22.5%) of intermediate-grade
malignancy, and two (5%) of high-grade malignancy; 20 cases (50%)
showed a low bone marrow infiltration (Bartl’s stage I), 11 (25%)
intermediate infiltration (stage II), and nine (22.5%) a high degree
of infiltration (stage III). Bone marrow biopsies from ten patients
with solid tumors but no bone marrow involvement were used as controls
for immunohistochemical analyses.
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All of the 58 bone marrow biopsies (48 MM and 10 controls) were fixed in B5 and decalcified by EDTA (Mielodec, Bio-Optica, Milan). The mean length of the biopsies was 15 mm (range, 7–28 mm). Cyclin D1 protein expression was assayed by means of the avidin-biotin peroxidase complex (ABC) method, using the 3,3'-diaminobenzidine tetrahydrochloride chromogen as previously described.30 For antigen retrieval, the slides were placed in 0.01 mol/L of EDTA buffer at pH 8.0 and underwent six 5-minute 780W cycles at 90°C in a microwave oven. The sections were immunostained with the DCS-6 monoclonal antibody (Novocastra Laboratories Ltd., Newcastle-on-Tyne, UK) at a working concentration of 1 µg/ml31 All of the bone marrow tissues were evaluated at 630x magnification and independently analyzed by two of the authors (G. P. and N. C.), who had no knowledge of the genetic and clinicopathological features. Only nuclear staining of cyclin D1 was considered positive. The percentage of cyclin D1-positive plasma cells was expressed as their ratio to the total number of plasma cells. In accordance with Vasef et al,26 we considered cyclin D1 to be positive if over 10% of plasma cells showed nuclear positivity. Formalin-fixed, paraffin-embedded samples from a laryngeal squamous cell carcinoma bearing a 20-fold BCL-1/cyclin D1 locus amplification,31 and EDTA-decalcified and B5-fixed samples from a bone marrow biopsy diffusely infiltrated by a mantle cell lymphoma, were used as positive control; the substitution of the primary antibody with nonimmune mouse serum was used as negative control.
FISH
FISH analyses were possible on 39 of the 48 patient samples and were performed as previously described.11 The percentage of malignant plasma cells, assessed by morphologically analyzing cytospins of cell suspensions from bone marrows, ranged from 13 to 85% (median, 31%). The bone marrow cells were cultured in RPMI 1640 medium supplemented with 20% fetal calf serum without any mitogen for 24 hours at 37°C in 5% CO2. The cultures were treated with colcemid (0.05 mg/ml) for 20 minutes. The cells were harvested using hypotonic potassium chloride, fixed by methanol/glacial acetic acid (3:1, v/v), and then stored at -20°C. Bone marrow cells from three healthy donors and three with thrombocythemia were used as negative controls.
The slides were hybridized in situ with probes labeled with biotin or directly with fluorochrome Cy3 (Amersham, Little Chalfont, UK) by means of nick translation as previously described.32 Biotin-labeled DNA was detected using fluorescein isothiocyanate (FITC)-conjugated avidin (green signal; Vector Laboratories, Burlingame, CA); direct Cy3 was detected as a red signal. The chromosomes were identified by simultaneous 4',6'-diaminido-2-phenylindole dihydrochloride (DAPI) staining, which produces a Q-banding pattern. Digital images were obtained using a Leica DMR epifluorescence microscope (Leica Imaging Systems Ltd., Cambridge, UK) equipped with a charge-coupled device camera (Cohu Inc., San Diego, CA). The FITC-avidin, Cy3, and DAPI fluorescence signals were detected using specific filters. The images were recorded, pseudocolored, and merged using QFISH software (Leica Imaging Systems Ltd, Cambridge, UK), and finally edited using Adobe Photoshop, Version 3 (Adobe Systems, Mountain View, CA).
FISH Probes
The 11q13 region was investigated using probes recently
described by us.9
In particular, the centromeric YAC 744
probe and the telomeric cosmid FGF3 probe were used in
double-color interphase and metaphase FISH, respectively giving red and
green signals. YAC 744 was obtained from the human CEPH2 library (YAC
Screening Center, DIBIT, Milan) and was reported to contain an insert
of approximately 300 kb and to be positive for the D11S97 and D11S146
markers located approximately 400 kb centromeric to the
MTC/BCL-1 locus.33,34
In addition, we have
previously shown that this YAC is retained on the der(11) chromosome in
KMS-12 cell line carrying the t(11;14) translocation,9
the
11q13 breakpoint of which has been localized 215 kb centromeric of the
BCL-1 locus.18
To our knowledge, this
breakpoint is the most centromeric so far cloned in MM. The clone
representative of the FGF3 locus, which is located
approximately 300 kb telomeric to the MTC/BCL-1 region, was isolated
from a cosmid library of human placenta (Clontech, San Diego,
CA).9
The two probes therefore bound a region of
approximately 600 kb, encompassing the BCL-1 and cyclin D1 loci
in which the majority of the 11q13 breakpoints in MM have so far been
identified or cloned.8,9,22,24
In normal chromosomes
the two signals are colocalized on 11q13, whereas breakpoints occurring
within this region should lead to the monoallelic segregation of the
two signals. The cutoff value for dissociated red and green signals
(neither associated physically nor yellow) in interphase FISH was
established as 10% (mean + 3SD) on the basis of the analysis of
200 nuclei from each negative control (4.67 ± 1.63).
Aneuploidy of chromosome 11 was evaluated using the biotin-labeled
-satellite DNA probe specific for chromosome 11 (clone D4Z1; Oncor
Inc., Gaithersburg, MD) on the same hybridization: the cutoff value for
11 trisomy was established as 1% (mean + 3SD) on the basis of the
analysis of 200 nuclei from each negative control (0.1 ± 0.3). To
determine whether the breakpoints were the result of a t(11;14)
translocation, the positive cases were analyzed by means of
double-color FISH using the FGF3 probe (red signal) and a
pool of plasmid clones previously reported by us11
that
are specific for the constant regions of the IGH locus
(IGH probe; green signal): the constant regions
C
1, C2, C3, C4 (BamHI/HindIII
fragments of 7, 4, 7, and 6 kb respectively), C1 and C2
(BamHI fragments of approximately 18 kb), and Cµ
(HindIII fragment of 10 kb). In the case of a
translocation the two signals colocalized in either interphase or
metaphase nuclei.
Statistical Analysis
The correlations between the clinicopathological and
immunohistochemical data were evaluated by means of Fischer exact test
or 
2
test with Yates correction when
necessary. For the purposes of statistical analysis, we considered two
cyclin D1 classes: positive and negative. The investigated
clinicopathological parameters were classified as follows: gender (male
and female); age at diagnosis (
60 years and >60 years); clinical
stage (I, II, and III); clinical symptoms (presence and absence);
Bartl’s histological grade (low and intermediate/high grade
malignancy); Bartl’s histological stage (I, <20% of bone marrow
infiltration; II, 20 to 50%; and III, >50%); lactic dehydrogenase
(LDH) (460 and >460 U/L); ß2 microglobulin (2.6 and >2.6
mg/ml).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty-eight MM patients were investigated, including 40 at
clinical presentation and 8 at relapse. The specificity of our IHC
assay for cyclin D1 expression was tested using ten normal bone marrow
biopsies as negative controls, and a bone marrow biopsy from a MCL case
as a positive control. Hematopoietic precursors and plasma cells from
negative controls were unreactive to cyclin D1 antibody (data not
shown), whereas intense nuclear staining was observed in the MCL case
(Figure 1A)
. Cyclin D1 expression was
found positive in the plasma cells of 12 (25%) MM patients (see Table 1
). The hematopoietic cells in the MM biopsies were also invariably
unreactive. Only three cases showed fewer than 10% positive plasma
cells, which appeared as scattered cells in the biopsy (a
representative case is shown in Figure 1B
); immunostaining was
localized to the nuclei of plasma cells and was variable in intensity
(see representative cases in Figure 1
, C–E).
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FISH analysis was possible in 39 of the 48 MMs. Red (YAC 744) and
green (FGF3) signals were found to be associated
(yellow signal) in the normal interphase and metaphase nuclei (Figure 2
, A and B), and the green signal from
the -satellite DNA probe specific for chromosome 11, which was used
on the same hybridization, could be easily distinguished from the
FGF3 signal in the interphase nuclei.
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). In all of these cases, associated
red and green signals were also found, thus suggesting the presence of
a normal chromosome 11; furthermore, no extra copies of chromosome 11
were found in any of the translocated cases as evaluated by the
-satellite DNA probe (see representative cases in Figure 2
, C and
G). Distinct patterns were detected in interphase nuclei from cases 34
and 47, which showed an additional green (FGF3) and
red (Yac 744) signal, respectively (see Figure 2
, E and I; see below).
Furthermore, FISH analysis demonstrated trisomy 11 in 13 cases (see
Table 1
), in all of which a third centromeric signal (green) was found,
together with a third series of associated red (Yac 744) and green
(FGF3) signals (see representative case in Figure 2K
).
FISH metaphases with dissociated YAC 744 and FGF3 signals
were found in five of seven cases with split signals in interphase
nuclei (cases 26, 34, 39, 47, and 48). In particular, case no. 34
showed a duplication of the reciprocal derivative chromosome, which
accounts for the third green (FGF3) signal observed
in interphase nuclei (Figure 2
, E and F). In case no. 47, dissociated
red (YAC 744) and green (FGF3) signals were detected
on one unidentified putative derivative chromosome, whereas a red
signal was still present on the putative der (11) chromosome (Figure 2
I and J); these findings may suggest the occurrence in this case of a
breakpoint within YAC 744 with the split of this region being followed
by a complex chromosomal rearrangement. In case no. 39, the putative
derivative chromosome containing the FGF3 signal showed a
large amount of extra telomeric material, again suggesting the
occurrence of a complex rearrangement (Figure 2H)
. The metaphases with
dissociated signals in case no. 48 (data not shown) had a pattern
apparently similar to that shown in Figure 2D
for case no. 26. Finally,
metaphases with three copies of chromosome 11 were found in five of the
13 cases with trisomy detected in interphase nuclei (see representative
case in Figure 2L
).
To determine whether these breakpoints were the result of a
t(11;14)(q13;q32) chromosomal translocation, we performed
double-color FISH using the FGF3 clone (red signal) and a
pool of the constant IGH regions (green signal). In all of
the seven cases with evidence of 11q13 breakpoints, we found associated
red and green signals in the interphase nuclei (see Figure 3A
for representative case). In case no.
34 (Figure 3C)
, the interphase nuclei showed the presence of two series
of colocalized green (IGH) and red
(FGF3) signals. The IGH-FGF3
colocalization was confirmed in four cases (nos. 26, 39, 47, and 48) on
metaphases (see Figure 3
, B and D; data not shown).
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Clinicopathological Parameters and Cyclin D1 Expression
On the basis of the correlation between cyclin D1 overexpression and t(11;14) translocation, we attempted a preliminary analysis of the relationship between cyclin D1 positivity and a series of clinicopathological variables available in our series. Cyclin D1 was expressed in 9 of the 40 MMs at diagnosis (22.5%) and in 3 of the 8 MM at relapse (37.5%; P = 0.654). In the patients at diagnosis, cyclin D1 positivity was more frequent in advanced than in early clinical stages: two of the 23 cases in stage I (8.7%); two of the six cases in stage II (33.3%); and five of the 11 cases in stage III (45.4%; P = 0.044). Moreover, cyclin D1 expression was more frequent in cases with clinical symptoms (8/22; 36.4%) than in those without (1/18; 5.5%; P = 0.026) and progressively increased with the extent of bone marrow infiltration, being detectable in two (10%) of the 20 cases in histological stage I (<20% bone marrow infiltration), two (18.2%) of the 11 cases in stage II (20 to 50% infiltration), and five (55.5%) of the nine cases in stage III (more than 50% infiltration; P = 0.022). No significant association was found in our series between cyclin D1 expression and histological grade (P = 0.399), although it was more frequently detected in cases of low grade (8/29; 27.6%) than in those of intermediate and high grade malignancy (1/11; 9.1%). Finally, no significant association was found between cyclin D1 expression and the variables of age, gender, LDH, or ß2 microglobulin serum levels.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breakpoints at 11q13 were detected in seven (18%) of the 39 cases investigated using interphase FISH; metaphases with dissociated signals were detected in only five of the positive cases. All of the 11q13 breakpoints were the result of a t(11;14) chromosomal translocation. The incidence of t(11;14) found in this study is similar to that (17%) recently reported by Avet-Loiseau et al,7 who based their FISH analysis on the colocalization of the IGH and 11q13 probes; these data therefore indicate that the t(11;14) occurs in approximately 20% of primary MM tumors. A further finding of our FISH analyses was the presence of trisomy 11 in 13 (33%) of the 39 investigated cases. Like two previous studies in which trisomy 11 was detected by means of interphase FISH in, respectively, 50% and 33% of cases,35,36 our study indicated that this numerical chromosome abnormality is more frequently associated with patients in advanced clinical stages. Finally, our data further support the use of interphase FISH for the detection of cytogenetic lesions in MM.
Although MM-derived cell lines have provided substantial evidence to suggest that the cyclin D1 gene may be deregulated in MM,8,9,22,24 information concerning its expression in representative series of primary MM tumors is limited and has not been correlated with the presence of t(11;14) translocation.25-27 We found cyclin D1 positivity by IHC in 25% of the tumors in our series, a frequency similar to the 26% reported by Vasef et al26 using the same method. Furthermore, we provide evidence that the t(11;14) translocation is strictly associated with gene deregulation; our combined analysis showed cyclin D1 expression in all of the seven cases bearing the t(11;14) translocation, in two of the 13 cases with trisomy 11 and in one of the 19 cases without apparent abnormalities of chromosome 11. Concerning the three cases showing cyclin D1 positivity but apparently negative for translocation, the most plausible explanation is that the breakpoints were outside the region investigated by our FISH. Furthermore, structural alterations other than translocation may be involved, as it has recently been reported by us and others that the breakpoint in the U266 MM-derived cell line occurs without any split of the 11q13 region but with the insertion of a part of the IGH locus.9,37 However, we did not observe any colocalization of the IGH-FGF3 probes in further FISH analyses of these three cases (data not shown). Alternatively, it is possible that currently unknown mechanisms may induce cyclin D1 expression in MM; in this regard, it has recently been shown by RT-PCR that cyclin D1 is expressed (albeit at lower levels) in non-Hodgkin’s lymphomas other than MCL and negative for the t(11;14).38
Overall, our study provides the first evidence that, as in MCL, the immunoreactivity to cyclin D1 can be considered a marker of the presence of t(11;14) in native MMs. Our data confirm previous evidence that normal plasma cells and hematopoietic precursors in bone marrow do not react to cyclin D1 antibody,26,38-40 thus further suggesting the specificity of this analysis. The immunohistochemical analysis of cyclin D1 may therefore be a reliable method of identifying patients with the t(11;14) and, in general, of demonstrating the involvement of this gene in MM. An important factor is that this approach can be adopted easily during routine diagnostic procedures and therefore seems to be superior to the double-color FISH insofar as it generally requires fresh material, cannot be used on archived material, and is beyond the scope of most pathology laboratories for technical reasons. In addition, it can be considered superior to the RT-PCR evaluation of cyclin D1 expression, which requires fresh or frozen material and is sometimes difficult to interpret because of its high degree of sensitivity and the variable percentage of myeloma cells in bone marrow. Taken together, these considerations suggest that IHC is the method of choice for the analysis of cyclin D1 involvement in MM.
Finally, the present study suggests that cyclin D1 overexpression may have prognostic significance in MM. Although we are aware that our series is relatively small, we observed that cyclin D1 expression significantly correlated with the degree of bone marrow involvement in primary tumors, because its incidence progressively increased with the extent of bone marrow infiltration, thus suggesting that it may give in vivo myeloma cells a growth advantage. In keeping with this, our analysis further indicated that cyclin D1 expression was significantly associated with an advanced clinical stage and the presence of clinical symptoms. The association with an advanced clinical stage is in agreement with reports concerning MM cases with t(11;14) and investigated by means of conventional cytogenetics alone,41,42 but not with those of the FISH studies recently described by Avet-Loiseau et al.7 Interestingly, a poor prognosis in MM was found to be significantly associated with abnormalities involving chromosome 11q.43 Further studies involving larger series of patients and an adequate followup are required to demonstrate whether cyclin D1 expression can be considered a prognostic marker in MM.
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Footnotes |
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Supported by grants from the Associazione Italiana sul Cancro (to A. N. and M. R.) and from the Ministero Italiano della Sanità (to Ospedale Maggiore IRCCS).
G. P. and S. F. contributed equally to this work.
G. P.’s present address: Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milano, Italy.
Accepted for publication February 8, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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