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PLENARY PAPER
From the Departments of Pathology and Microbiology, The
Munroe-Meyer Institute for Genetics and Rehabilitation, Preventive and
Social Medicine and Internal Medicine, University of Nebraska Medical
Center, Omaha; Metabolism Branch, Division of Clinical Sciences,
National Cancer Institute, National Institutes of Health, Bethesda, MD;
and Departments of Pathology, Biochemistry, and Medicine, Stanford
University Medical Center, Stanford, CA.
Recently we have identified subgroups of de novo primary diffuse
large B-cell lymphoma (DLBCL) based on complementary DNA microarray-generated gene expression profiles. To correlate the gene
expression profiles with cytogenetic abnormalities in these DLBCLs, we
examined the occurrence of the t(14;18)(q32;q21) in the 2 distinctive
subgroups of DLBCL: one with the germinal center B-cell gene expression
signature and the other with the activated B cell-like gene expression
signature. The t(14;18) was detected in 7 of 35 cases (20%). All 7 t(14;18)-positive cases had a germinal center B-cell gene expression
profile, representing 35% of the cases in this subgroup, and 6 of
these 7 cases had very similar gene expression profiles. The expression
of bcl-2 and bcl-6 proteins was not significantly different between the
t(14;18)-positive and -negative cases, whereas CD10 was detected only
in the group with the germinal center B-cell expression profile, and
CD10 was most frequently expressed in the t(14;18)-positive cases. This study supports the validity of subdividing DLBCL into 2 major subgroups
by gene expression profiling, with the t(14;18) being an important
event in the pathogenesis of a subset of DLBCL arising from germinal
center B cells. CD10 protein expression is useful in identifying cases
of DLBCL with a germinal center B-cell gene expression profile and is
often expressed in cases with the t(14;18).
(Blood. 2002;99:2285-2290) The t(14;18)(q32;q21) is believed to play a
crucial role in the pathogenesis of follicular lymphoma because it
deregulates the expression of the antiapoptotic gene
BCL2 by bringing it into proximity of the
immunoglobulin heavy chain gene enhancer.1-3 The
t(14;18)(q32;q21), with its associated BCL2
gene rearrangement, has also been detected in up to one third of
cases of primary diffuse large B-cell lymphoma (DLBCL).4-8
However, it is not known whether cases with the t(14;18) represent a
unique subset of DLBCL or what role this translocation plays in their
pathogenesis. We have recently shown that gene expression patterns can
delineate 2 major subgroups of DLBCL.9 One subgroup has an
expression profile resembling that of normal germinal center (GC) B
cells, the GC B cell-like (GCBL) type. The other subgroup has a
profile resembling that of peripheral blood B cells activated by
mitogenic stimuli, the activated B cell-like (ABL) type. If the
t(14;18) is the initiating pathogenic event in primary DLBCL, we
hypothesized that these lymphomas will have a GC B-cell gene expression
profile. Therefore, we examined our patients with DLBCL with gene
expression data to determine the role of the t(14;18) in the
pathobiology of DLBCL.
Patient population, tumor samples, and gene expression profiling by
complementary DNA microarray
Detection of the t(14;18)(q32;q21) by fluorescence in situ
hybridization
Detection of BCL2 gene rearrangement by polymerase chain reaction Of 35 cased studied by FISH, 30 cases had high-molecular-weight DNA available for polymerase chain reaction (PCR) analysis. Amplification of the BCL2/JH translocation at the major breakpoint region (mbr) and the minor cluster region (mcr) was performed as described by Sharp et al10 using an OminiGene thermocycler (Hybaid, Middlesex, United Kingdom). Positive controls consisted of DNA extracted from the human B-cell lymphoma line RL-7 for the mbr of BCL2, and DHL-16 for the mcr of BCL2. Negative controls consisted of sterile water instead of DNA, and DNA from normal peripheral blood mononuclear cells obtained from healthy volunteer donors. Standard precautions were taken to guard against PCR contamination, and amplified materials were analyzed in a laboratory physically separated from the one where unamplified materials were handled.11Immunohistochemistry for CD10, bcl-2, and bcl-6 Formalin-fixed, paraffin-embedded 5-µm sections were stained with the avidin-biotin-peroxidase complex (ABC) method.12 Antigen retrieval was performed by incubation for 30 to 60 minutes in 10 mM citrate buffer (pH 6.0) in a 95°C hot water bath followed by 20 minutes of cooling at room temperature (32 cases from Nebraska), or using EDTA buffer at pH 8.0 for CD10 and bcl-6 (3 cases from Stanford). Antibodies to the following antigens were used: CD10 (clone 56C6, Ventana, Tucson, AZ, for cases from Nebraska; or Novocastra, Newcastle upon Tyne, United Kingdom, for cases from Stanford), bcl-2 (clone 24; Dako, Carpinteria, CA), and bcl-6 (polyclonal, Santa Cruz Biotechnology, Santa Cruz, CA, for cases from Nebraska; or PG-B6p, Dako, for cases from Stanford). A tumor was considered to be positive for expression of a specific antigen if more than 10% of the tumor cells showed appropriate immunoreactivity.Statistical analysis The Fisher exact test was used to compare the frequencies of the t(14;18) in the GCBL and ABL subgroups of DLBCL. This test was also used to compare the frequencies of CD10, bcl-2, and bcl-6 protein expression in the t(14;18)-positive and -negative subgroups of DLBCL. The survival analysis was performed on cases with and without t(14;18) using log-rank test. The Student t test was used to compare the microarray measurements of gene expression levels between the t(14;18)-positive and -negative subgroups of DLBCL. Genes differentially expressed between the 2 groups were selected with a cutoff of P < .05. The ratio of specific gene expression in the t(14;18)-positive cases versus the t(14;18)-negative cases of the GCBL subgroup was calculated by dividing the mean fluorescence intensity of the t(14;18)-positive by the mean fluorescence intensity of the t(14;18)-negative GCBL cases. Agglomerative hierarchical clustering was performed using the CLUSTER program (M. Eisen: http://www.microarrays.org/software).13
Occurrence of the t(14;18) in DLBCL To define the subset of DLBCL with the t(14;18), we applied interphase FISH to nuclei isolated from tumor tissues (Figure 1). Of the 35 cases studied, a t(14;18) was detected in 7 of 20 cases (35%) of GCBL-DLBCL but in none of 15 cases of ABL-DLBCL (P = .01, Fisher exact test; Figure 2). Using PCR, we found BCL2/JH gene rearrangements in 3 of 5 t(14;18)-positive cases by FISH, which is similar to our detection rate in follicular lymphoma. None of the t(14;18)-negative cases by FISH had a BCL2/JH rearrangement by PCR.
Patients with the t(14;18) included 6 women and 1 man ranging from 59 to 81 years of age at the time of diagnosis. There was no significant difference in overall survival when these 7 patients were compared with the t(14; 18)-negative patients in the entire group (P = .35) or in the GCBL group (P = .99), but the number of cases studied is small. Bcl-2, bcl-6, and CD10 protein expression To further characterize the cases, we performed immunohistochemistry to determine the expression of bcl-2, bcl-6, CD10, and CD20 proteins. These results are summarized in Table 1. The frequencies of bcl-2 protein expression were not significantly different between the GCBL (15 of 20, 75%) and ABL (10 of 15, 67%) subgroups of DLBCL (P = .46). Four of 7 t(14;18)-positive cases (57%) and 21 of 28 t(14;18)-negative cases (75%) of DLBCL showed bcl-2 protein expression in the tumor cells. This finding indicates that the t(14;18) does not always lead to bcl-2 protein expression and that bcl-2 expression is often present in DLBCL in the absence of the t(14;18). Expression of bcl-6 protein was detected in 30 of 35 cases (86%) of DLBCL and showed no significant association with any subgroup. However, CD10 protein was detected in 11 of 20 cases (55%) in the GCBL subgroup, including 6 of 7 with the t(14;18) (86%), and none in the ABL subgroup (P < .001). Protein expression data for the 7 cases with the t(14;18) is shown in Table 2. All 7 cases with the t(14;18) showed expression of bcl-6 protein, but not always detectable bcl-2 or CD10 protein by immunohistochemistry.
Gene expression profile associated with the t(14;18) in DLBCL All 7 cases with the t(14;18) by FISH had the GC gene expression signature. Six of these cases, all positive for CD10 protein expression, had very similar gene expression patterns and formed a tight cluster together with normal GC B cells and the t(14;18)-positive cell line SUDHL-6 in the dendrogram (Figure 2). However, one t(14;18)-positive case (DLCL-0003), which was negative for CD10 and bcl-2 protein expression, was located outside of this tight cluster, indicating a substantial difference in its overall gene expression pattern. BCL2 gene expression was quite variable and generally low in GCBL-DLBCL as compared to the reference pool when hybridization to clones 1336385 and 342181 were examined (Figure 3). When the sequences of the 3 different bcl-2 cDNA clones (232714, 342181, 1336385 ) used for microarray analysis were examined, only clone 232714 was able to consistently detect the bcl-2 transcripts in t(14;18)-positive lymphomas and the t(14;18) lymphoma cell line SUDHL-6. This clone contained a cDNA fragment from the middle portion of BCL2 gene and can hybridize to truncated transcripts from cases with bcl-2 translocation at the mbr. When we examined BCL2 gene expression as indicated by cDNA clone 232714, we found that 6 of 7 t(14;18)-positive DLBCL cases show overexpression (the exception being the outlying case DLCL-0003). The case (DLCL-0018) with translocation at the mcr showed concordant results with all the clones. A group of t(14;18)-negative cases in both the GCBL and ABL groups also had high levels of bcl-2 transcripts, which are detected by all 3 cDNA clones as expected.
To search further for genes differentiating the t(14;18)-positive from
t(14;18)-negative cases of GCBL-DLBCL, all genes on the Lymphochip
(4026 clones) including GC B cell-associated genes were compared
between the 7 cases with the t(14;18) and the 13 cases of GCBL-DLBCL
without the t(14;18). We identified genes or expressed sequence tags
(ESTs) represented by 403 cDNA clones showing significant
differential expression (P < .05) using the 2-tailed
Student t test. Genes or ESTs represented by 251 clones were
expressed at higher levels in the t(14;18)-positive cases, whereas
other genes or ESTs represented by 152 clones were expressed at lower
levels in the t(14;18)-positive cases (Figure
4). The 10 most differentially expressed
genes are listed in Table 3.
The t(14;18)(q32;q21) translocation is a characteristic feature of follicular lymphoma and is thought to be the initiating event in lymphomagenesis.14,15 By analogy, DLBCL with the same translocation may be related to follicular lymphoma and the t(14;18) may also be important in its pathogenesis. In this study, we looked for the presence of the t(14;18) in a series of DLBCL using 2 techniques, FISH and PCR. The FISH assay has a higher sensitivity and detected the t(14;18) in 20% (7 of 35 cases) of DLBCL. Interestingly, these cases occurred exclusively in the GCBL subgroup, wherein the frequency was 35% (7 of 20 cases). Six of these 7 cases clustered closely with each other, and with normal GC cells and the t(14;18)-positive lymphoma cell line SUDHL-616 in the dendrogram, indicating very closely related gene expression profiles. The fact that these 6 cases shared a unique translocation and had gene expression profiles that were very similar to those of normal GC cells provides strong evidence that DLBCL with the t(14;18) is a distinctive subset within the GCBL subgroup. This observation also supports the validity of subdividing DLBCL into the GCBL and ABL subgroups, and indicates that tumors sharing an important genetic abnormality may also share a distinctive gene expression profile. We also examined the messenger RNA (mRNA) and protein expression patterns of bcl-6 and CD10 because of their known association with normal and neoplastic GC B cells. The bcl-6 protein was expressed in all cases with the t(14;18), but it was also expressed in a high percentage of the remaining cases. CD10 was highly expressed at the mRNA level and frequently detected at the protein level in GCBL-DLBCL, but none of the cases of the ABL subgroup expressed CD10 by protein immunohistochemistry. These results suggest that CD10 protein expression is a specific, but not a very sensitive, marker for GCBL-DLBCL. Moreover, CD10 protein expression was demonstrated in a high percentage (86%) of the t(14;18)-positive cases. Some of our t(14;18)-positive DLBCLs did not show detectable bcl-2 protein expression by immunohistochemistry, in keeping with previously published reports. Kramer et al17 reported that 12 of 25 cases of DLBCL with BCL2 gene rearrangement had low or absent expression of bcl-2 protein. In the study reported by Tang et al,18 only 2 of 15 cases of DLBCL with the BCL2 gene rearrangement were found to have a high level of bcl-2 protein expression. It is possible that bcl-2 expression is essential early in lymphomagenesis, but additional genetic abnormalities developing during tumor progression may abrogate the requirement for bcl-2. The mechanisms for dissociation between BCL2 gene rearrangement and bcl-2 protein expression are unclear. At the transcription level, bcl-2 expression was quite variable and showed no dependence on the presence of t(14;18). In t(14;18)-positive cases of DLBCL, bcl-2 transcripts were up-regulated in 6 of 7 cases with a probe that can detect bcl-2 mRNA in cases with BCL2 translocation at the mbr. Case DLCL-00003, which was negative for both bcl-2 and CD10 expression, showed a very low or undetectable level of bcl-2 transcripts with all cDNA clones. A group of t(14;18)-negative cases in both GCBL and ABL groups showed high levels of bcl-2 transcripts detected by all cDNA clones, indicating that alternative mechanisms up-regulating bcl-2 expression are operative in these cases. A set of genes differentially expressed between GCBL-DLBCL with and without the t(14;18) can be identified by statistical analysis (Figure 4 and Table 3). However, due to the small number of cases compared in our study, these results are considered preliminary and further analysis in a larger study is necessary to identify differentially expressed genes at a high level of confidence. How is primary DLBCL with a t(14;18) different from follicular lymphoma
that typically has a t(14;18)? In this study, the t(14;18)-positive
cases of DLBCL were carefully reviewed and no follicular structures
were seen morphologically or by immunostaining for follicular dendritic
cells. Furthermore, none of these patients had a prior history of
follicular lymphoma. Therefore, these cases are not follicular
lymphomas misdiagnosed as DLBCL. The fact that primary DLBCLs with the
t(14;18) have gene expression profiles similar to normal GC B cells
suggests that the t(14;18) plays an important role in the pathogenesis
of this subset of DLBCL, just as it does in follicular lymphoma. The
t(14;18) is thought to occur as a low-frequency error during
IGH gene rearrangement in normal B-cell maturation,
resulting in abnormal bcl-2 overexpression, which allows the cells to
escape apoptosis if they become GC B cells. However, the t(14;18) is
not sufficient for neoplastic transformation. In fact, rare cells with
the t(14;18) are detectable in tonsils, lymph nodes with follicular
hyperplasia, and blood lymphocytes from healthy
individuals.19,20 These GC B cells harboring the t(14;18)
are able to undergo repeated cycles of clonal expansion when the
appropriate antigen is encountered. Extensive proliferation introduces
additional genetic changes that lead to neoplastic transformation. The
different genetic abnormalities occurring during this phase may lead to
follicular lymphoma or primary DLBCL. We illustrate this concept in
Figure 5.
It is likely that a number of different genetic lesions can result in the development of DLBCL from a t(14;18)-positive GC B cell, and each of these genetic alterations may be associated with a unique gene expression signature. One could speculate that the outlying case DLCL-0003 with the t(14;18) was associated with a different transformational event than the other 6 cases that clustered tightly together. We believe that genetic and gene expression analysis of additional cases will allow us to define the critical genetic events that lead to neoplastic transformation of GC B cells.
We thank Grant Wu and Greg Cochran for technical assistance.
Submitted July 20, 2001; accepted November 9, 2001.
Supported in part by grants U01-CA84967 and CA34233 from the National Cancer Institute and grant 6605-01 from the Leukemia and Lymphoma Society.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Wing C. Chan, Dept of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198; e-mail: jchan{at}unmc.edu.
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Y. Shen, J. Iqbal, J. Z. Huang, G. Zhou, and W. C. Chan BCL2 protein expression parallels its mRNA level in normal and malignant B cells Blood, November 1, 2004; 104(9): 2936 - 2939. [Abstract] [Full Text] [PDF]
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S. Bea, L. Colomo, A. Lopez-Guillermo, I. Salaverria, X. Puig, M. Pinyol, S. Rives, E. Montserrat, and E. Campo Clinicopathologic Significance and Prognostic Value of Chromosomal Imbalances in Diffuse Large B-Cell Lymphomas J. Clin. Oncol., September 1, 2004; 22(17): 3498 - 3506. [Abstract] [Full Text] [PDF]
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J. Iqbal, W. G. Sanger, D. E. Horsman, A. Rosenwald, D. L. Pickering, B. Dave, S. Dave, L. Xiao, K. Cao, Q. Zhu, et al. BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma Am. J. Pathol., July 1, 2004; 165(1): 159 - 166. [Abstract] [Full Text] [PDF]
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J. Houldsworth, A. B. Olshen, G. Cattoretti, G. B. Donnelly, J. Teruya-Feldstein, J. Qin, N. Palanisamy, Y. Shen, K. Dyomina, M. Petlakh, et al. Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas Blood, March 1, 2004; 103(5): 1862 - 1868. [Abstract] [Full Text] [PDF]
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Z. Pan, Y. Shen, C. Du, G. Zhou, A. Rosenwald, L. M. Staudt, T. C. Greiner, T. W. McKeithan, and W. C. Chan Two Newly Characterized Germinal Center B-Cell-Associated Genes, GCET1 and GCET2, Have Differential Expression in Normal and Neoplastic B Cells Am. J. Pathol., July 1, 2003; 163(1): 135 - 144. [Abstract] [Full Text] [PDF]
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D. de Jong, A. M. Glas, L. Boerrigter, M.-C. Hermus, O. Dalesio, E. Willemse, P. M. Nederlof, and M. J. Kersten Very late relapse in diffuse large B-cell lymphoma represents clonally related disease and is marked by germinal center cell features Blood, July 1, 2003; 102(1): 324 - 327. [Abstract] [Full Text] [PDF]
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S. L. Barrans, P. A. S. Evans, S. J. M. O'Connor, S. J. Kendall, R. G. Owen, A. P. Haynes, G. J. Morgan, and A. S. Jack The t(14;18) Is Associated with Germinal Center-derived Diffuse Large B-Cell Lymphoma and Is a Strong Predictor of Outcome Clin. Cancer Res., June 1, 2003; 9(6): 2133 - 2139. [Abstract] [Full Text] [PDF]
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J. Greeve, A. Philipsen, K. Krause, W. Klapper, K. Heidorn, B. E. Castle, J. Janda, K. B. Marcu, and R. Parwaresch Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas Blood, May 1, 2003; 101(9): 3574 - 3580. [Abstract] [Full Text] [PDF]
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M. Sanchez-Beato, A. Sanchez-Aguilera, and M. A. Piris Cell cycle deregulation in B-cell lymphomas Blood, February 15, 2003; 101(4): 1220 - 1235. [Abstract] [Full Text] [PDF]
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I. S. Lossos, A. A. Alizadeh, R. Rajapaksa, R. Tibshirani, and R. Levy HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma Blood, January 15, 2003; 101(2): 433 - 440. [Abstract] [Full Text] [PDF]
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L. Colomo, A. Lopez-Guillermo, M. Perales, S. Rives, A. Martinez, F. Bosch, D. Colomer, B. Falini, E. Montserrat, and E. Campo Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma Blood, January 1, 2003; 101(1): 78 - 84. [Abstract] [Full Text] [PDF]
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A. Rosenwald, G. Wright, W. C. Chan, J. M. Connors, E. Campo, R. I. Fisher, R. D. Gascoyne, H. K. Muller-Hermelink, E. B. Smeland, J. M. Giltnane, et al. The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma N. Engl. J. Med., June 20, 2002; 346(25): 1937 - 1947. [Abstract] [Full Text] [PDF]
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I. Magrath Molecular Characteristics of Diffuse Large-B-Cell Lymphoma N. Engl. J. Med., June 20, 2002; 346(25): 1998 - 1999. [Full Text] [PDF]
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Top
Abstract
Introduction
), whereas (NA)
indicates that no material was available for FISH study.
