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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3498-3506 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.025 Clinicopathologic Significance and Prognostic Value of Chromosomal Imbalances in Diffuse Large B-Cell LymphomasFrom the Hematopathology Section, Laboratory of Pathology and Hematology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi I Sunyer, University of Barcelona, Barcelona; and Information and Studies Service, Department of Health and Social Security, Barcelona, Spain Address reprint requests to Elias Campo, Laboratory of Pathology, Hospital Clínic, Villarroel 170, 08036-Barcelona, Spain; e-mail: ecampo{at}clinic.ub.es
PURPOSE: To determine the clinicopathologic significance and prognostic value of chromosomal imbalances in diffuse large B-cell lymphomas (DLBCL). PATIENTS AND METHODS: We have examined 64 tumors at diagnosis using comparative genomic hybridization and real-time quantitative polymerase chain reaction (PCR), single-stranded conformational polymorphism, and DNA sequencing for the analysis of several potential target genes. RESULTS: The most recurrent alterations were gains of 18q (20%), Xq (15%), 2p, 7q, and 12p (14%), and losses of 6q and 17p (14%). Frequent high-level DNA amplifications were detected at 2p13-p16 and 18q21 loci. Real-time quantitative PCR detected REL and BCL11A gene amplifications in the nine patients with gains at 2p13-p16 and only in one additional patient with normal chromosome 2. Similarly, the BCL-2 gene was amplified in the 12 tumors with gains of 18q21 but in none of 39 patients with normal 18q profile. p53 gene inactivation was detected in nine of 58 (16%) tumors and was commonly associated with 17p losses. Tumors with 18q gains were significantly associated with a high number of chromosomal imbalances, primary nodal presentation, high serum lactate dehydrogenase levels, high International Prognostic Index, shorter cause-specific survival, and a high risk of relapse. Losses of 17p and p53 gene alterations were associated with an absence of complete response achievement. CONCLUSION: These results suggest that DLBCLs have a characteristic pattern of genomic alterations; 18q gains or amplifications and 17p losses are associated with particular clinicopathological features and aggressive clinical behavior. Additional studies are needed to confirm these observations in larger series of patients.
Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of neoplasms with diverse clinical and biologic characteristics. This diversity has already been recognized in the WHO classification in which several clinicopathologic subtypes and morphological variants have been identified.1 These tumors have an aggressive clinical behavior. Approximately 50% of the patients may be cured with current treatments but most of the remaining patients will eventually die as a result of the disease.2 Clinical prognostic parameters, including the International Prognostic Index (IPI), are used to stratify patients according to the overall prognosis.3 However, the individual prognostic categories include patients with heterogeneous prognoses. The genetic and molecular mechanisms underlying the diverse clinical presentation and biologic behavior of these lymphomas are not well known. A better understanding of these mechanisms may improve the prognostic assessment and clinical management of the patients. Cytogenetic studies of DLBCLs have revealed a broad spectrum of clonal genetic abnormalities and complex karyotypes, including chromosomal translocations, deletions, duplications, and other undefined alterations.4-8 These aberrations probably involve target genes that may play an important role in the development and progression of these tumors.5 The complex spectrum of genetic alterations detected in these lymphomas is concordant with their clinical and biologic heterogeneity. Some of these alterations have been associated with particular morphologic variants of DLBCL6 or clinical and prognostic characteristics of the patients.7-11 However, these findings generally have been poorly reproducible or even contradictory. Most of these studies were performed before the Revised European-American Lymphoma and WHO classifications of lymphoid neoplasms were extensively used and may have included heterogeneous groups of patients. Conversely, molecular cytogenetic techniques such as comparative genomic hybridization (CGH),12-15 multicolor fluorescence in situ hybridization,16,17 and spectral karyotyping17,18 are providing a more comprehensive view of the genetic alterations in these tumors. Several studies of different lymphoid neoplasms have demonstrated that the complexity of genomic imbalances and individual chromosomal abnormalities detected by CGH are associated with particular clinical manifestations of the patients and are important prognostic parameters.19-23 However, the potential clinical relevance of these alterations in DLBCLs has not been well defined. In this study, we have investigated a series of primary DLBCLs by CGH to evaluate the potential clinicopathologic significance and prognostic value of genomic aberrations in these tumors. We have also examined the molecular alterations of different potential target genes included in the chromosomal regions more commonly altered in these tumors.
Patients Sixty-four previously untreated patients (39 males and 25 females; median age, 62 years) diagnosed with de novo DLBCL at our hospital were selected. The diagnosis of DLBCL and different histological subtypes was based on previous defined criteria.1,24,25 The B-cell phenotype was confirmed in all patients by immunohistochemistry.25 All of the patients were treated and had follow-up visits at the same institution. The criteria for inclusion were the availability of appropriate frozen tissue and a tumor cell content higher than 85%. Patients with a previous indolent lymphoma with subsequent transformation into a DLBCL; immunodeficiency-associated tumors; primary mediastinal, CNS, intravascular, or primary effusion lymphoma; and T-cell–rich B-cell lymphoma were excluded. Approval was obtained from the Institutional Review Board for these studies. The tumors had a primary extranodal origin in 22 patients. The proportion of patients with poor performance status and B symptoms was 38% and 46%, respectively. The distribution by Ann Arbor stage was I, 12%; II, 29%; III, 21%; and IV, 38%. Thirty-nine patients presented with any extranodal site involved, including 13 patients with bone marrow infiltration. The distribution according to the IPI in the 63 patients with complete data was the following: low risk, 22 patients (35%); low-intermediate risk, 16 patients (25%); high-intermediate risk, nine patients (14%); and high risk, 16 patients (25%).3 Fifty-eight patients (88%) received doxorubicin-containing regimens, in most cases cyclophosphamide, doxorubicin, vincristine, and prednisone. Among the 63 patients in whom the response was assessable, 34 (55%) achieved complete response (CR), nine (14%) achieved partial response, and 20 (32%) failed to respond. After a median follow-up of 5.4 years (range, 0.9 to 11.6 years), 39 patients had died, with a median overall survival (OS) of 2.3 years, and a 5-year OS of 40% (95% CI, 27% to 53%).
CGH
Molecular Analysis
A mutational analysis of exons 4 to 8 of the p53 gene was performed in 58 patients. Individual exons were amplified by PCR using specific primers, a single-stranded conformational polymorphism analysis, and direct sequencing as described.26 An analysis of the BCL-2/JH rearrangement at the major breakpoint region and minor cluster region was performed for 52 patients.25
Statistical Analysis
CGH Aberrations in DLBCL DNA imbalances were observed in 43 (67%) of 64 patients with DLBCL (Fig 1 and Table 2). Low copy number gains (n = 123) were more frequent than losses (n = 50) and high-level DNA amplifications (n = 21). High-level DNA amplifications were detected in 15 loci of 14 different tumors. The mean number of alterations per patient was 2.9 ± 3.8 standard deviations (SDs): 1.8 ± 2.4 SDs for gains, 0.3 ± 0.7 SDs for high-level DNA amplification, and 0.8 ± 1.1 SDs for losses.
Five patients showed complex CGH karyotypes with multiple alterations (12 to 15 alterations per patient), whereas single chromosome imbalances were detected in 11 (26%) of 43 patients with CGH alterations. Two of these patients had a gain in chromosome 12. The nine remaining patients had different single alterations: gains of 1q, 2p14, 2q23-qter, 3q, 10p, and 18q, and losses of 8p23, 14q24-qter, and 17p. Recurrent chromosomal gains involved 18q (20%); Xq (15%); 2p, 7q, 12p, (14%); 1q, 3q, 6p, 11q, 12q, and Xp (12%); and 7p and 8q (11%; Table 2). The minimal common regions of gain were 18q21, Xq25-qter (patient 62), 2p13-p14, 7q21-q22, 12p11, 3q26-qter, 11q25, 12q13, Xp22, 7p15-pter, and 8q24. The most common recurrent high-level DNA amplification was at 2p13-p16 (6%), followed by 18q21-q23 (5%), and 6p25 and Xp22 (3%). Patients with gains of 18q by CGH (n = 13) wereassociated with a significantly higher number of total CGH imbalances than tumors with a normal chromosome 18 profile (n = 51; mean 7.5 ± 5 SDs v 1.7 ± 2.2 SDs, respectively; P < 0.001). Recurrent chromosomal losses consisted of 6q and 17p (14%), and 13q and Xp (8%), with minimal common regions in 17p13 and 6q21-q22. Chromosome 13q and Xp showed both losses and gains. Interestingly, tumors with losses of chromosome 17p (n = 9) had a significantly higher number of total imbalances than tumors with a normal chromosome 17 profile (n = 55; mean, 7.8 ± 4.7 SDs v 2 ± 3 SDs, respectively; P = .03). Similarly, losses of chromosome 6q (n = 9) were also associated with a higher number of total imbalances than a normal chromosome 6 profile (n = 55; mean, 7.7 ± 5 SDs v 2 ± 3 SDs, respectively; P = .04). Only two tumors showed 17p and 6q losses simultaneously (patients 6 and 34) and showed high numbers of CGH alterations (nine and 15, respectively). Several alterations seemed to be either associated with each other or were mutually exclusive. In that sense, 18q and Xq gains were detected in 13 and 10 patients, respectively, but only one patient (patient 48) showed both alterations simultaneously. Conversely, 3q gains were associated with gain of 18q because six of eight patients (75%) with 3q gains also showed a gain of 18q.
Correlation Between CGH Results and Molecular Studies
The nine tumors with an amplification (n = 4) or gain (n = 5) of the 2p13-p16 region showed a simultaneous amplification or gain, respectively, of both REL and BCL11A genes by RQ-PCR (Table 3 and Fig 2A). In addition, RQ-PCR was able to detect a gain of REL and BCL11A genes in patient 23 with a normal chromosome 2 profile. In each individual case, the genomic dose of these two genes was in the same range of amplification. The other 20 patients with a normal chromosome 2 by CGH did not show any increased dose of REL and BCL11A genes (Table 3).
The four patients with an amplification of 18q21 by CGH showed an increased BCL-2 gene copy number by RQ-PCR with ratios of 1.5 to 6 (Table 3 and Fig 2B). The eight tumors with gains of 18q also had increased BCL-2 gene copies with ratios of 1.4 to 3. A normal BCL-2 gene dose was detected in the 39 additional patients examined with no alterations in 18q. These results indicate a good relationship between the RQ-PCR results for REL, BCL11A, and BCL-2 genes and the CGH profile of the 2p and 18q regions, respectively (Table 3). BCL-2/JH rearrangement was studied in 51 patients. Four patients (8%) showed BCL-2/JH rearrangement at major breakpoint or minor cluster regions. Two of these patients also showed a gain of 18q21 by CGH and an amplification of BCL-2 gene by RQ-PCR.
p53 gene alterations were detected in nine (16%) of the 58 patients examined. Six tumors showed point mutations and three tumors shown a homozygous deletion of the gene. Seven of these nine patients had a loss of 17p by CGH, whereas a wild-type p53 gene was detected in two additional patients with 17p losses and in the remaining patients with normal chromosome 17 profile. The six mutations consisted of missense single-base substitutions in five patients (at nucleotide positions S380Y, R742G, R743W, R745G, and R817C) and one truncating mutation that consisted of a 1-bp deletion (
Correlation Between CGH Alterations and Clinicopathological Characteristics of the Patients BCL-2 protein overexpression was detected in 32 (63%) tumors by immunohistochemistry, nine of 12 (75%) patients with BCL-2 gene amplification, 21 of 34 (62%) patients with wild-type BCL-2 gene, and two additional patients with the t(14;18). Unexpectedly, three (25%) of 12 patients with BCL-2 gene amplification did not show BCL-2 protein expression. The total number and individual chromosomal alterations was compared with the clinical characteristics of the patients at diagnosis and their evolution after treatment. (Table 4) Patients with 18q gains exhibited more often a primary nodal origin (92% v 59%; P = .02). They also showed more frequently high serum lactate dehydrogenase levels (83% v 50%; P = .05) and a high-risk IPI score (62% v 16%; P = .003). No other clinical relationships were observed (stage, Eastern Cooperative Oncology Group performance status, general state, age, and sex).
Regarding the response to treatment, the CR rate was lower in the 13 patients with 18q gain or amplification by CGH compared with those patients with normal chromosome 18, but this did not reach statistical significance (31% v 59%; P = .1). Conversely, only one of the eight patients (12%) with 17p loss by CGH achieved a CR compared with 32 (52%) of the patients with no loss of 17p (P = .02). Similarly, p53 gene alterations were also associated with treatment failure (P = .04). The predictive value of the different CGH alterations was analyzed separately. Patients with gain of 18q showed a poor cause-specific OS compared with those with normal chromosome 18 (5-year cause-specific OS, 20% v 47%, respectively; P = .04; Fig 3A). Moreover, among the 34 patients who achieved a CR, the risk of relapse was higher in patients with 18q gain than in the others (risk of relapse at 5 years, 75% v 19%, respectively; P = .002; Fig 3B). When the analysis was restricted to the 41 patients with primary nodal localization, patients with gain of 18q showed a higher risk of relapse (P = .0005) and also a poor OS (P = .01). In addition, patients with p53 gene alteration showed a tendency toward a shorter cause-specific survival than patients without this alteration (P = .06).
Finally, to assess the clinical significance of 18q gain or amplification by CGH, a multivariate Cox analysis was performed including both IPI and 18q gain. In the model to predict the risk of relapse, with both variables available in 32 patients, 18q gain kept its prognostic significance (P = .004; relative risk, 11.7) along with the IPI (low risk v intermediate and high risk; P = .055; relative risk, 4).
The chromosomal imbalances detected in our series were relatively similar to those found in other studies.12,14,30 Recurrent gains mainly involved 18q, Xq, 2p, 7q, and 12p, whereas the most common losses targeted 6q and 17p. Among all chromosomal alterations, only 18q gains were associated with particular clinical features of the patients at diagnosis. Thus, overrepresentation of 18q was significantly associated with a primary nodal presentation, high serum lactate dehydrogenase, and high IPI score. In addition, 18q gains were also more commonly found in tumors with a higher number of global chromosomal imbalances. Regarding the follow-up, patients with 18q gains showed a significantly shorter cause-specific OS, higher risk of relapse, and a tendency to lack a CR to treatment. This relationship between 18q gains and parameters of more aggressive behavior in DLBCL has not been well recognized previously. Interestingly, a recent study in follicular lymphomas identified a distinct clinical presentation in patients with 18q gains, although with no differences were observed in the outcome.22 In another study, dup(18q) was found to predict an unfavorable OS in follicular lymphomas with the t(14;18) translocation.31 18q gain has been observed as a frequent single chromosomal imbalance in follicular lymphomas or as the only alteration associated with the t(14:18) translocation.22,32 In our study, 18q gain was observed as a single alteration in one patient and associated with only a second chromosomal alteration in two additional patients. However, tumors with 18q gains also had a significantly higher number of chromosomal imbalances than did patients with normal chromosome 18 profile. Conversely, Berglund et al12 observed 18q gains in relapsed DLBCL more commonly than in primary tumors. These findings suggest that 18q gains may be a relatively early alteration in a subset of DLBCL and may confer a selective advantage associated with progression of the disease and more aggressive behavior. However, because of the relatively small number of patients, additional studies are needed to confirm the clinicopathologic significance of these alterations in larger series of patients. The minimal common region gained in chromosome 18 included band 18q21 where BCL-2 gene is located. BCL-2 gene amplification has been reported previously in DLBCL with 18q21 high-level DNA amplifications14,15,30,33,34 suggesting that this gene may be an important target of this amplicon. In our study, RQ-PCR analysis confirmed the close relationship between 18q21 gains by CGH and BCL-2 gene amplification because all patients with over-representation of this region had an increased number of BCL-2 gene copies, whereas a normal CGH profile was always associated with a normal BCL-2 gene signal. However, BCL-2 gene may not be the target in all types of DLBCL because BCL-2 amplification was not identified in primary CNS DLBCL35 or primary mediastinal large B-cell lymphomas30 with 18q amplifications. Some studies have suggested that BCL-2 gene amplification and the t(14;18) translocation may represent mutually exclusive alterations in DLBCL,36,37 whereas these alterations may occur simultaneously in a subset of follicular lymphomas.38,39 In our series, a BCL-2/JH rearrangement was detected in four patients, two of them also carrying 18q gains by CGH. This relative low frequency of BCL-2/JH rearrangement (8%) detected by PCR is similar to that found in other studies.36,40-42 BCL-2 gene rearrangement and amplification have been associated with mRNA and/or protein expression in DLBCL.36,37 In our series, BCL-2 protein expression was observed in the four patients with BCL-2 gene rearrangements and almost all patients with gene amplification. However, three patients with 18q gains and BCL-2 gene amplification were repetitively negative for BCL-2 protein expression, suggesting that other genes located in 18q21 may be the target of this amplicon in some DLBCL. In this sense, target genes other than BCL-2 have been observed recently in transformed follicular lymphomas with 18q gains.15,43 In addition to 18q gains, 17p losses and p53 gene inactivation were also associated with complex karyotypes and parameters of poor prognosis, particularly a lack of complete response to standard treatment and a trend toward a shorter cause-specific survival. These results are concordant with previous studies indicating that inactivation of the p53 gene is associated with clinical progression, poor prognosis, drug resistance, and low rates of complete remission in patients with aggressive B-cell lymphomas.44 In our study, there was a relatively good correlation between 17p losses and p53 gene inactivation, suggesting that p53 must be the main target gene of this genetic alteration. The diversity of chromosomal aberrations in our series was similar to that found in other studies of DLBCL. However, the incidence of particular aberrations showed some differences in comparison with other series that may be related to a certain relationship between particular chromosomal alterations and the topographic origin of the tumors. Thus, the lack of 9p gains in our series is concordant with the exclusion of primary mediastinal B-cell lymphomas in which this alteration is the most frequent genetic finding.30,45,46 Chromosome 12 gains were also found less frequently than in other studies. However, this alteration seems particularly common in primary gastric DLBCL,47,48 and in our study we had only three primary gastric lymphomas that also had chromosome 12 gains. Two major types of DLBCL have been recognized by cDNA microarray expression profile that may correspond to different clinical and biologic entities.49 Additional studies are needed to determine whether these subtypes of DLBCL are associated with particular chromosomal alterations. Previous studies have recognized chromosomal and gene amplification as a relatively frequent phenomenon in DLBCL.15 In the present series, we have identified 21 high-level DNA amplifications in 15 different regions. Most of these amplifications have been observed in other DLBCLs and non-Hodgkin's lymphomas. However, we had found two novel high-level DNA amplifications at 4p15 and 10q11. The most common amplified region in addition to 18q21 was 2p13-p16. Gain of chromosome 2p has been identified as a recurrent alteration in different types of DLBCLs,46,50 and represents the most frequent CGH alteration in classical Hodgkin's lymphoma.51,52 The consensus region is 2p14-p16 where the REL oncogene is located.53 REL amplification has been found in DLBCL,15,43 gastrointestinal DLBCL,48 primary mediastinal DLBCL,46 transformed follicular lymphomas,15,43 and Hodgkin's lymphoma.51,52 In addition, REL amplification was a genetic characteristic of the germinal center-like DLBCL identified by gene expression profile.49 In addition to REL, the minimal region of gain also contains BCL11A, a candidate oncogene involved in lymphomagenesis. Similarly to BCL6, BCL11A encodes for a specific germinal center gene that functions as a transcriptional repressor. BCL11A and BCL6 interact directly and may control the same subgroup of genes in mature B cells.54,55 BCL11A gene status has not been analyzed previously in DLBCL. BCL11A also has been found amplified in Hodgkin's lymphoma.56 However, REL, rather than BCL11A, seems to be the target of the 2p13 alterations in this neoplasm. In our study, we observed coamplification of both REL and BCL11A in all patients with 2p amplification or gain, suggesting that both genes may be targets of this amplicon. Additional studies are needed to clarify the particular contribution of these two genes in the pathogenesis of DLBCL. In conclusion, we have investigated the clinical significance and prognostic value of chromosomal aberrations detected by CGH in a series of patients with DLBCL. The results suggest that 18q gains and BCL-2 gene amplification, and, to a lesser extent, 17p losses and p53 gene inactivation, are associated with particular clinicopathologic features of the patients at presentation and may define a subset of tumors with more aggressive clinical behavior.
The authors indicated no potential conflicts of interest.
We thank Montse Sanchez and Iracema Nayach for their excellent technical assistance.
Supported by grants SAF 2002/03261 from Comisión Interministerial de Ciencia y Tecnología, PI030473 from Fondo Investigación Sanitaria (FIS), Redes Temáticas de Centros de Cáncer (C03/110) y estudio de linfomas (G03/179) from FIS, Instituto de Salut Carlos III, and Generalitat de Catalunya 2000SGR00118. S.B. was supported by Fundació Internacional José Carreras (FIJC/01). M.S. was supported in part by Dakocytomation. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 were considered as gene gain and amplification, respectively. 
455) in patient 6, resulting in a stop codon (FS506STOP). Patients with p53 gene alteration were associated with a significantly higher number of total chromosomal imbalances compared with tumors with no mutation (mean, 8.8 ± 5 SDs v 2 ± 2.7 SDs, respectively; P = .005). 
