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From the Departments of Pathology and Microbiology, Internal Medicine, and Preventive and Societal Medicine, and Eppley Cancer Institute,* University of Nebraska Medical Center, Omaha, Nebraska; the Departments of Pathology and Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; the Department of Pathology, University of Würzburg, Würzburg, Germany; the Metabolism Branch and Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; the Department of Computer Science,¶ University of Nebraska at Omaha, Omaha, Nebraska; the Department of Pathology,|| Norwegian Radium Hospital, Oslo, Norway; the Department of Pathology,** University of Oregon Health Sciences Center, Portland, Oregon; the Department of Pathology, Hospital Clinic, University of Barcelona, Barcelona, Spain; and the Department of Pathology, University of Arizona, Tucson, Arizona
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Abstract |
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25,000 cases in the United States. DLBCL is a heterogeneous entity both clinically and morphologically. We have recently shown by gene expression profiling that DLBCL can be classified into two major subgroups.1
The germinal center B-cell-like (GCB) subgroup expresses genes characteristic of normal GC B cells and is associated with a good outcome after multiagent chemotherapy, whereas the activated B-cell-like (ABC) subgroup expresses genes characteristic of activated blood B cells and is associated with a poor clinical outcome. Nonetheless, considerable molecular heterogeneity exists within each subgroup. A small number of DLBCL cases are unclassifiable and do not express the GCB or ABC signature genes at a high level.2
More recently, primary mediastinal large B-cell lymphoma (PMBL) has been identified as a distinct subgroup of DLBCL that can be distinguished by gene expression profiling from GCB- and ABC-DLBCL.3,4 The t(14;18)(q32;q21) is a characteristic feature of follicular lymphoma and is considered to be the initiating event in lymphomagenesis. The t(14;18) is the result of an error during the process of VDJ recombination, leading to deregulation of the expression of the anti-apoptotic gene BCL2 by bringing it into proximity of the immunoglobulin heavy chain (IgH) gene enhancer.5-8 In our initial study of 35 cases of DLBCL, we correlated BCL2 translocation data with gene expression profiles and showed that the t(14;18) defines a unique subset of DLBCL within the GCB subgroup.9 This observation suggested that important genetic lesions are associated with a unique, identifiable gene expression profile. To substantiate and further extend this finding, we have examined 141 new cases that were part of 240 cases of DLBCL studied by cDNA microarray for molecular predictors of survival after chemotherapy.2 These 141 cases of DLBCL with gene expression profiles, clinical data, and genetic data for BCL2 translocation were studied to determine: 1) the distribution of the t(14;18) among the subgroups of DLBCL identified by gene expression profiling; 2) whether t(14;18)-positive cases have a unique gene expression profile; and 3) whether there are differences in the tumor characteristics and clinical behavior between cases with and without the t(14;18).
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Materials and Methods |
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We studied 240 previously analyzed cases of DLBCL with clinical data and gene expression profiles determined by complementary DNA (cDNA) microarray technology.2 A panel of hemopathologists including E Campo, ES Jaffe, G Ott, HK Müller-Hermelink, J Delabie, R Gascoyne, T Grogan, DD Weisenburger, and WC Chan confirmed the diagnosis of DLBCL and excluded the presence of follicular lymphoma in all patients. Informed consent was obtained and the Institutional Review Board of the University of Nebraska approved this study.
Preparation of Tissue Microarrays (TMAs) and Immunohistochemical Studies
TMAs were prepared from cases with adequate archival paraffin-embedded tissue. Hematoxylin and eosin-stained sections from each paraffin-embedded, formalin-fixed block were examined to define diagnostic areas and two to five (average, four) representative 0.6-mm cores were obtained from each case and inserted in a grid pattern into a recipient paraffin block using a tissue arrayer (Beecher Instruments, Silver Spring, MD). Five µm sections were then cut from each TMA and stained with antibodies to BCL2, BCL6, and CD10 as described.10 CD20 stains were performed to evaluate each core for involvement by tumor, and each case was evaluated independently by two pathologists (CPH, DDW) for the percentage of tumor cells stained and recorded in 10% increments. Disagreements were resolved by joint review on a multihead microscope. For each case, the core with the highest percentage of tumor cells stained was used for analysis. Cases were considered positive if 30% or more of the tumor cells were stained with an antibody.10
Detection of the t(14;18)(q32;q21) by Fluorescence in Situ Hybridization (FISH)
Among the 240 cases studied by gene expression profiling, 129 cases were studied by interphase FISH for the presence of the t(14;18)(q32;q21). To perform FISH studies, 4-µm sections were cut from the TMA paraffin blocks and mounted on positively charged slides. The sections were dewaxed in three changes of HEM-D (Scientific Safety Solvents, Keller, TX) followed by dehydration in 95% ethanol. They were then treated with 0.2 N HCl for 15 minutes, rinsed in distilled-deionized water, and incubated in a sodium thiocyanate solution at 80°C for 15 minutes. After rinsing in phosphate-buffered saline (PBS), the sections were digested with a protease solution at 37°C for 10 minutes; postfixed in 0.95% formaldehyde solution/PBS with 0.45% MgCl2 for 5 minutes at room temperature; rinsed in PBS; and sequentially dehydrated in 70%, 80%, and 95% ethanol.
For FISH, the dual-color LSI IgH Spectrum Green/LSI BCL2 Spectrum Orange Dual-Fusion Translocation Probe (Vysis, Downers Grove, IL) was used to detect the t(14;18), and the CEP 18 Spectrum Aqua probe (Vysis) was used simultaneously to evaluate the chromosome 18 copy number. The probe mixture (10 µl) was placed on the tissue sections, coverslipped, and sealed. Hybridization was performed overnight at 37°C using an automated hybridization chamber (HYBrite, Vysis) after denaturation at 75°C for 5 minutes. The slides were washed in 2x standard saline citrate/0.1% Nonidet P-40 for 2 minutes at 72°C and then at room temperature for 2 minutes. Nuclei were counterstained with 4,6-diamidino-2-phenylindole at a concentration of 125 ng/ml in anti-fade solution and the slides were visualized using an Olympus BX52 fluorescence microscope. Images were captured and archived using Cytovision software (Applied Imaging, Santa Clara, CA). To analyze the hybridization, a total of 50 to 100 nuclei were scored per case for the presence of the t(14;18). In normal cells, an interphase nucleus will exhibit individual red (BCL2) and green (IgH) signals. When the t(14;18) occurs, the red and green signals form two yellow fusion signals in the interphase cell. It has been established by the University of Nebraska Medical Center Human Genetics Laboratories that reactive lymphoid tissues show <2% positive cells at 2.5 SD for this FISH assay.
Detection of BCL2 Gene Rearrangement by Polymerase Chain Reaction
Extracted DNA from all 240 cases was tested for the t(14;18) by the polymerase chain reaction (PCR). Amplification of the BCL2/JH translocation at the major breakpoint region (mbr) and minor cluster region (mcr) was performed as described previously.11 Positive controls consisted of DNA extracted from the human B-cell lymphoma cell lines RL-7 for the mbr and DHL-16 for the mcr. Negative controls consisted of sterile water instead of DNA, and DNA from normal peripheral blood mononuclear cells obtained from healthy donors. Standard precautions were taken to guard against PCR contamination. The PCR-positive cases were added to the FISH-positive cases to form a final set of 34 cases with the t(14;18). The FISH-negative cases comprised the t(14;18)-negative group.
Analysis of Differential Gene Expression
We used the recently published Bayesian classification system to define the GCB, ABC, and unclassifiable subgroups of DLBCL.12 We also separated cases with the PMBL gene expression profile3 into a new subgroup, and examined the t(14;18) within each of these subgroups. The presence or absence of the BCL2 translocation was used to supervise the discovery of differentially expressed genes between the t(14;18)-positive and -negative cases in the GCB subgroup. The two-tailed Student’s t-test was used to compare the differences in gene expression levels. Genes differentially expressed between the two subsets with a P value of <0.01 were selected for further analysis using the Significance Analysis of Microarrays (SAM) approach, as described previously.13 In addition to the P value, we also calculated the t-statistics between the two groups and only genes that differed by a magnitude of >2.6 were selected for further analysis.
As previously described, of the three different BCL2 clones (232714, 342181, 1336385) on the Lymphochip microarray, only clone 232714 with a more 5' sequence could detect message with a truncated 3' end because of translocation at the mbr. Overexpression of BCL2 as measured by clone 232714 was highly correlated with the BCL2 translocation. However, clone 232714 is located far from the 3' end of the transcript and, therefore, may fail to measure much of the cDNA transcribed by reverse transcription reactions starting from the poly-A tail of the normal BCL2 transcript. We used the mean values measured by the BCL2 clones that are located close to the 3' end (342181, 1336385) of the transcript to represent the gene expression level in cases in which this mean value was greater than the measurement by clone 232714.
Survival Analysis
The Kaplan-Meier method was used to estimate the overall and event-free survival of the patients, and the log-rank test was used to compare the survival experiences between the t(14;18)-positive and -negative cases. Overall survival was defined as the time from diagnosis to death from any cause or, for patients remaining alive, the time from diagnosis to last contact. Event-free survival was defined as the time from diagnosis to the first occurrence of relapse or death from any cause or, for patients remaining alive and relapse-free, the time from diagnosis to last contact. SAS software (SAS Institute Inc., Cary, NC) was used for the data analysis.
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Results |
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Based on the results of our recent study of PMBL,3
12 GCB cases were reclassified as PMBL. Therefore, we classified the DLBCL cases into GCB, ABC, PMBL, and unclassifiable subgroups and examined the distribution of the t(14;18). Interphase FISH was applied to the 129 TMA cases and detected 22 cases that were positive for the t(14;18). Based on FISH analysis, t(14;18) was detected in 17% (22 of 129) of the cases of DLBCL which represented 34% (19 of 55) of the cases in the GCB subgroup. We also performed PCR assays on 240 cases studied by cDNA microarray, 26 cases were found to be positive, including 14 of the cases previously found to be positive by FISH (Figure 1)
. The PCR-negative cases that were not tested by FISH were excluded from further analysis because of the recognized high false-negative rate of the PCR assay. Thus, PCR analysis revealed an additional 12 positive cases and in this cohort of 141 cases, 34 DLBCL cases carried the t(14;18) translocation, and 107 lacked this abnormality (Figure 1)
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We reviewed the immunohistochemical reactions of 109 TMA samples to correlate the presence and absence of the t(14;18) translocation with the expression of three relevant proteins, namely BCL-2 (encoded by the gene deregulated by the translocation) and two markers of normal germinal center B cells (BCL6 and CD10).
The protein expression of BCL2 was similar in the GCB (28 of 50, 56%) and ABC (19 of 31, 61%) subgroups, but was less frequent in the unclassifiable (6 of 19, 31%) or the PMBL subgroups (2 of 9, 22%). The difference did not reach statistical significance (P = 0.054) (Table 1)
. Within the GCB subgroup there was a significant difference (P < 0.0001) in BCL2 protein expression between thet(14;18)-positive cases (88%) and t(14;18)-negative cases (24%) (Table 2)
indicating that the t(14;18) is highly associated with BCL2 protein expression in this subgroup. In other subgroups BCL2 was generally up-regulated by mechanisms other than the t(14;18), as frequently seen in the ABC cases.
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. CD10 protein expression was detected overall less commonly than BCL6 (28%, 31 of 109), and the great majority of these cases (26 of 31) were in the GCB subgroup (Table 1)
. This accounted for the fact that CD10 expression was much commoner overall in t(14;18)-positive cases than in t(14;18)-negative cases (67% versus 15%; P < 0.0001) (Table 2)
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To search for genes that are differentially expressed between the t(14;18)-positive and t(14;18)-negative cases in the GCB subgroup, we examined all informative genes among 7399 known or uncharacterized genes on the Lymphochip.2
Clones with a P value of <0.01 were selected for SAM analysis.13
Among the 146 clones selected, 53 clones were overexpressed in the t(14;18)-positive group and 93 clones were overexpressed in the t(14;18)-negative group. The genes that were overexpressed in the t(14;18)-positive group represented a heterogeneous set including genes involved in apoptosis (BCL2, BAD, DRAK1, and TXBP151), a number of transcription factors (FLI1, HOX11, and BAP135) and genes associated with cell adhesion/migration (CD62L, cytohesin-1, profilin 2, SDF1, and CD31). Interestingly, a large number of genes overexpressed in the t(14;18)-negative group are associated with cell cycle progression and regulation (Figure 3A)
. These include genes that control several events in mitosis (PLK, KNSL5, TTK, P55CDC, ARK2, CENE, and CENF), genes involved in cell cycle progression (CYCLIN-A, CDC2, CDC25C, and SAK) and DNA replication (HMG-I/Y, DNA helicase, and DHFR).
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. Correlation between the t(14;18) and Survival in the GCB Subgroup
The GCB subgroup (excluding PBML) consisted of 39 men and 26 women with a median age of 61 years (range, 24 to 88 years). The median follow-up of the surviving patients was 7.3 years (range, 0.8 to 21.8 years) in this group. Figure 4, A and B
, shows Kaplan-Meier estimates of overall and event-free survival experiences, respectively, of the t(14;18)-positive and negative subsets of the patients in the GCB subgroup as defined by the Bayesian classifier. P values are based on a log-rank comparison of the outcome of the two subsets. There is no significant difference between the two cytogenetic subsets.
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Discussion |
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We also analyzed the immunohistochemical findings available in the cases with t(14;18) data. The vast majority of patients with this translocation had increased BCL2 protein expression. However, BCL2 protein was also frequently present in cases without the translocation, especially in the ABC subgroup, which characteristically had high BCL2 mRNA levels. This indicates that up-regulation of BCL2 expression may occur by other mechanisms such as activation of the nuclear factor-kB pathway or an increased copy number of the BCL2 gene. It is interesting to note that, in the GCB subgroup, BCL2 protein expression was markedly different in cases with and without the t(14;18) (89% versus 37%, respectively). BCL6 protein was more frequently expressed in the GCB versus the ABC and other subgroups, but was not specifically correlated with the t(14;18) within the GCB subgroup. On the other hand, CD10 expression was highly specific for the GCB subgroup and was most frequently expressed in cases with the t(14;18). In the PMBL subgroup, the majority have the immunohistochemical profile of the t(14;18)-negative cases, as expected.
We also attempted to correlate the t(14;18) status with gene expression profiles within the GCB subgroup to discover genes that characterize the two cytogenetic subsets and might provide insight into their pathobiology. SAM analysis was used to find genes that were differentially expressed between the two subsets after an initial data reduction based on the Student’s t-test (P < 0.01). SAM analysis identified 53 up-regulated genes in the t(14;18)-positive cases and 93 up-regulated genes for t(14;18)-negative cases. BCL2 gene expression is an important discriminator between the two cytogenetic subsets. BCL2 was overexpressed in most cases of GCB-DLBCL with the t(14;18). However, there were a few cases in which BCL2 expression was low, indicating that overexpression of this gene may no longer be necessary in some cases of established DLBCL. The microarray analysis was further substantiated by BCL2 immunohistochemistry, which revealed that a high percentage (88%) of t(14;18)-positive GCB-DLBCL cases had BCL2 protein expression, whereas BCL2 was expressed in only 24% of the t(14;18)-negative cases. In addition to BCL2, several genes that may be involved in apoptosis were also overexpressed in t(14;18)-positive cases including BAD, a proapoptotic gene in the BCL2 family. DRAK1, a positive mediator of apoptosis, is related to Death-associated Protein Kinase 1 (DAP1).15 TXBP151 is a novel anti-apoptotic gene that has been shown to mediate the activity of A20, which is induced by CD40/CD40L interaction,16,17 and its proteolysis is associated with FAS-mediated apoptosis. IL15 was also overexpressed in the BCL2 translocated cases and it has been implicated in protecting B cells from apoptosis.18 The precise functional alterations in the apoptotic pathway are difficult to predict from the gene expression data and it is possible that the apoptotic pathway is dominated by BCL2 overexpression in the vast majority of t(14;18)-positive cases. In addition to these genes, there is also overexpression of a heterogeneous group of transcription factors including FLI1 that regulates expression of the TGF-ß type II receptor,19 HOX11 that belongs to a family of DNA-binding transactivators,20 and BAP135. BAP135 exists as a complex with Bruton Tyrosine Kinase (BTK) before B-cell antigen receptor engagement and is transiently tyrosine-phosphorylated in response to B-cell receptor cross-linking.21 BAP135 is identical to the putative transcription factor TFII-I and there is evidence that tyrosine phosphorylation may enhance its activity, thereby linking receptor activation with changes in gene expression. A group of genes that have diverse functions were also overexpressed including a number of genes that are involved in cell adhesion, migration, and cytoskeletal function: CD62L, cytohesin-1, profilin 2, SDF1, and CD31. CD62L is involved in cell adhesion and migration.22 Cytohesin-1 is a guanine nucleotide exchange factor for ARF GTPases and is a regulator of integrin-mediated cell adhesion.23 The function of integrins is regulated through cytoplasmic signaling, and profilin 224 may form an important link between integrin cell adhesion signals and F-actin polymerization, as has been postulated in T lymphocytes.25 SDF1 is a highly potent lymphocyte chemoattractant and is also involved in intracellular actin polymerization in lymphocytes, a prerequisite for cell motility.26 CD31 has widespread distribution and in addition to cell adhesion, may have a role in regulating cell signaling and angiogenesis.27,28
The gene expression profile associated with t(14;18)-negative cases was dominated by genes involved in cell cycle progression and regulation. These included genes involved in regulating mitotic spindle functions, activation of anaphase promoting complex (APC) and events essential for cytokinesis (eg, PLK, mitotic kinesin-like protein-1, or KNSL5, P55CDC, and CKS1).29-32 In addition to these genes, many important regulators of cell cycle-related events including centrosome separation/segregation (eg, ARK2),33 kinetochore association (eg, CENF),34 functional components of mitotic check points (eg, CENPE and TTK orMps1),35,36 chromatin association and DNA replication (eg, HMG-I/Y, chromatin assembly factor-I (p150), DNA helicase and DHFR).37-39 A group of genes that promotes G2/M transit or are expressed in the M phase of the cell cycle, including CYCLIN-A, CDC2, CDC25C, and SAK,40-42 were also up-regulated. These results suggest that t(14;18)-negative GCB-DLBCL is significantly more mitotically active than the t(14;18)-positive cases, and indicates that the two cytogenetic subsets have distinctive biological characteristics. In normal cells, BCL2 has been reported to retard G1/S phase progression43 and the higher expression of BCL2 in the translocated cases may have the same effects on cell cycle progression as has been observed in developing B lymphocytes.44 However, further studies are needed to determine whether other mechanisms are involved in the higher expression of genes associated with cell cycle regulation and progression in the nontranslocated subset.
Overall and failure-free survival analysis did not show any significant differences between t(14;18)-positive and -negative cases within the GCB subgroup. However, there seems to be a continued occurrence of late deaths in the t(14;18)-positive subset but this finding needs to be confirmed in a larger series of patients.
In conclusion, we found that t(14;18) was present in a large subset of cases in the GCB-DLBCL subgroup. This specific translocation was primarily confined to GCB-DLBCL, without any cases seen in ABC-DLBCL, thus supporting the view that DLBCL can be divided into pathogenetically distinct subgroups with unique gene expression profiles. Cases in the ABC subgroups also frequently overexpressed BCL2, but through mechanisms other than t(14;18). The t(14;18)-positive subset within the GCB subgroup showed a clear decreased expression of proliferation signature genes when compared with the t(14;18)-negative subset. This could be partly explained by the anti-proliferation effect of BCL2, but there may be other underlying biological mechanisms. These two subsets did not show any significant differences on survival under conventional therapy. However, the increase in BCL2 expression in one subset and the higher proliferative activity in the other suggest biological differences that could be exploited in future clinical trials.
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Acknowledgements |
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Footnotes |
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Supported in part by United States Public Health Service grants CA36727 and CA84967 awarded by the National Cancer Institute, Department of Health and Human Services.
Accepted for publication March 24, 2004.
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