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(American Journal of Pathology. 2001;158:1843-1850.)
© 2001 American Society for Investigative Pathology

Regular Articles

Novel Genomic Imbalances in B-Cell Splenic Marginal Zone Lymphomas Revealed by Comparative Genomic Hybridization and Cytogenetics

Jesús María Hernández^*, Juan Luis García^*, Norma Carmen Gutiérrez^*, Manuela Mollejo, José Angel Martínez-Climent, Teresa Flores^*, María Belén González^*, Miguel Angel Piris and Jesús F. San Miguel^*

From the Servicio de Hematología,^*
Hospital Universitario and Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca; the Servicio de Anatomía Patológica,
Hospital Virgen de la Salud, Toledo; and the Servicio de Hematología y Oncología Médica,
Hospital Clínico Universitario, Valencia, Spain

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Splenic marginal zone lymphoma (SMZL) has recently been recognized in the World Health Organization classification of hematological diseases as distinct type of non-Hodgkin’s lymphoma. In contrast to the well-established chromosomal changes associated with other B-cell non-Hodgkin’s lymphoma, few genetic alterations have been found associated with SMZL. The aim of our study was to analyze by comparative genomic hybridization (CGH) the chromosomal imbalances in 29 patients with SMZL and to correlate these findings with clinical and biological characteristics and patient outcome. In 21 cases, cytogenetic studies were simultaneously performed. Most of the patients (83%) displayed genomic imbalances. A total of 111 DNA copy number changes were detected with a median of four abnormalities per case (range, 1 to 12). Gains (n = 92) were more frequent than losses (n = 16), while three high-level amplifications (3q26-q29, 5p11-p15, and 17q22-q25) were observed. The most frequent gains involved 3q (31%), 5q (28%), 12q and 20q (24% each), 9q (21%), and 4q (17%). Losses were observed in 7q (14%) and 17p (10%). SMZL patients with genetic losses had a shorter survival than the remaining SMZL patients (P < 0.05). In summary, chromosomal imbalances in regions 3q, 4q, 5q, 7q, 9q, 12q, and 20q have been detected by CGH in SMZL. Patients with SMZL displaying genetic losses by CGH had a short survival.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

Comparative genomic hybridization (CGH) is a double-color hybridization procedure that provides, in a single experiment, a general view of genomic imbalances, including partial or complete trisomies, monosomies, or amplifications within the tumor genome.¹³ This technique can be used to identify previously unexpected genetic abnormalities. Several groups have studied chromosomal changes by CGH in different subtypes of B-cell NHL.^14-16 Thus, in marginal zone lymphomas, gains on chromosomes 3 and 18 are frequent.¹⁷ In extranodal lymphomas such as gastrointestinal lymphomas, total or partial gains of chromosomes 11, 12, and 1q are frequently observed.¹⁸ However, little is known about the genomic imbalances in SMZL.

The present study was designed to screen DNA copy changes by CGH in a series of 29 SMZL and to correlate the results obtained from CGH with the most relevant clinical, biological, and cytogenetic characteristics, including disease outcome.

	Materials and Methods

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Patients

Tumor specimens from 29 patients with SMZL were included in the study. All cases were classified according to the criteria proposed by Isaacson and colleagues¹⁹ and Mollejo and colleagues.² All samples were studied at diagnosis and were reviewed and classified by three of the authors (MM, TF, and MAP).

Cytogenetics

Cytogenetic studies were available in 21 patients. Most chromosome analyses were performed on the spleen (11 cases), whereas in six cases studies were performed on peripheral blood, in three cases on the lymph nodes, and in the remaining case, on the bone marrow. Cytogenetic analysis of the splenic tissue was performed after 24 and 48 hours of culture without stimulating agent, and 48 hours culture stimulated with phorbol 12-myristate 13-acetate. Peripheral blood and bone marrow cells were cultured for 3 days in presence of phorbol 12-myristate 13-acetate. Metaphases were G-banded and karyotypes were described according to the International System of Human Cytogenetic Nomenclature.²⁰ At least 20 mitoses were analyzed in each patient.

CGH

Tumor DNA was isolated from the spleen (25 cases), peripheral blood (2 cases), or bone marrow (2 cases). Reference DNA was obtained from peripheral blood lymphocytes of healthy donors (same sex as patients). The phenol-chloroform method was used for DNA extraction according to standard procedure.²¹ CGH analysis was performed according to the method described by Lichter and Ried²² Briefly, tumor DNA (test DNA) was labeled with biotin-16-dUTP (Boehringer Mannheim, Mannheim, Germany) and normal DNA (reference DNA) was labeled with digoxigenin-11-dUTP (Boehringer Mannheim) by a standard nick translation reaction. The size of the nick-translated fragments ranged from 300 to 1,000 bp. Equal amounts (1 µg) of labeled tumor and normal DNAs, and 70 µg of unlabeled human Cot-1 DNA (Life Technologies, Inc., Gaithersburg, MD) were co-hybridized to slides with human metaphase chromosome spreads prepared from phytohemagglutinin-stimulated lymphocytes from normal individuals. After hybridization for 1 to 2 days in a moist chamber at 37°C, posthybridization washes were performed to a stringency of 0.1x standard saline citrate at 42°C. Tumor and normal DNA were detected by avidin-fluorescein isothiocyanate and rhodamine-conjugated anti-digoxigenin, respectively. The slides were counterstained with 4,6-diamidino-2-phenylindole and mounted with an antifade solution. Image acquisition was performed with an epifluorescence microscope (Olympus BX60) equipped with a cooled charge-coupled device camera. Calculation of the tumor DNA to normal DNA fluorescent ratios along the length of each chromosome was performed by means of an automated CGH software package (Cytovision; Applied Imaging, Sunderland, UK). Ratio values obtained from at least 10 metaphase cells for each case were averaged. Ratio values >1.25 and <0.75 were considered to represent chromosomal gain and loss, respectively. Overrepresentation was defined as high-level amplification when the profile exceeded the cut-off value of 1.5. Chromosomal gains exceeding 1.5 involving the whole chromosome or large areas of a chromosomal arm were not considered as high-level DNA amplification. Negative control experiments were performed using differentially labeled male versus male and female versus female DNA. Additional control experiments included the interchange of the digoxigenin-dUTP and biotin-dUTP labels between normal and tumor DNA. According to previous recommendations, we measured the average number of copy alterations (ANCA) index.²³ This index represents the average number of copy alterations in a tumor type and is calculated by dividing the total number of copy alterations by the number of tumors analyzed.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Patients

The most relevant clinical data from the 29 patients is shown in Table 1 . No sex predominance was observed (male to female,14 to 15) and the median age was 64 years (range, 39 to 79 years). According to the Ann-Arbor classification, all patients presented with advanced stage because of bone marrow infiltration. However, only 20% of patients displayed high levels of serum lactic dehydrogenase (normal value, 460 IU/L). In 43% of cases, a lymph node involvement was present. Lymphocytosis was present in 55% of patients. All but two patients (cases 26 and 27) received a splenectomy and in 10 cases, chemotherapy was administrated. Overall survival of the whole series was 72 months (95% CI, 44 to 100 months). At the time of the study, 18 patients remained alive (Table 1) .

In 16 of the 21 patients (76%) in which cytogenetic studies were available, an abnormal karyotype was present. Most cases were pseudodiploid. In two cases (cases 6 and 25) the modal number of chromosomes was more than 49. Only one case (case 8) had a hypodiploid karyotype. Seven out of the 16 patients (44%) had a complex karyotype. The most frequent cytogenetic abnormality was deletion of 7q (six cases) whereas a trisomy of chromosome 3 was observed in only three cases. Trisomies of chromosomes 5 and 12 were detected in two cases, respectively. Several chromosomal breakpoints were found to be repetitively involved in SMZL patients. Thus, abnormalities involving 7q22-q33 were detected in seven cases; whereas rearrangements in 1p22, 1q21, and 5q31, were found in two patients each.

CGH

Twenty-four of the 29 patients with SMZL (83%) showed DNA sequence copy number changes and five cases displayed normal profiles. A total of 111 DNA copy number changes were detected with a median of four abnormalities per case (range, 1 to 12): 92 gains, 16 losses, and three high-level amplifications (Figure 1) . All abnormal cases except cases 14, 22, and 23 showed more than one chromosomal imbalance (Table 2) . In 19 patients, overepresentations of chromosomal material were detected. Gains of chromosomal material involved 3q (31%), 5q (28%), 12q and 20q (24% each), 9q (21%), 4q (17%), and 11q and 12p (14% each). The consensus regions of gains were located at 3q23-q25, 4q25-q28, 5q13-q15, 9q31, 12q15-q21, and 20q. In 10 cases (35%), a genetic loss was present. In four of the 10 cases, the losses of chromosomal material were the only changes detected. Losses were located in 7q (14%) with a commonly deleted region at 7q31-q32, 17p (10%), and 8p, 13q, and 15q (7% each) (Figure 1) . Only three cases showed high-level amplifications located at 3q26-q29, 5p11-p15, and 17q22-q25. These amplifications were located in chromosomal regions in which known fragile sites have been identified (3q26-29 and FRA3C, 5p11-p15 and FRA-5A, and 17q22-25 and FRA17B). As indicated in Material and Methods, ANCA index represents the average number of copy alterations in a tumor type. In the present study, the ANCA index was 3.8.

View larger version (36K): [in this window] [in a new window]   Figure 1. Summary of the genomic imbalances in 29 patients with SMZL. Left: Lines indicate loss of chromosomal material. Right: Lines indicate gain of chromosomal material. High-level DNA amplifications are represented as solid squares. Each line represents a gained or lost region in a single tumor. The numbers on top of each line refer to the patient analyzed.

Correlation between CGH Results and Outcome

A correlation between losses and a shorter survival was found. Thus, the patients displaying a loss of chromosomal material had a survival of 36 months while the patients without losses had a longer survival (101 months, P = 0.02) (Figure 2) . By contrast, patients with deletions assessed by conventional cytogenetics did not show differences in survival in relation with patients without deletions (76 versus 46 months, P = 0.78). Patients with SMZL and more than four changes detected by CGH did not present differences in survival from the cases of SMZL with less than four changes (60 months versus 80 months, respectively, P = 0.8).

View larger version (13K): [in this window] [in a new window]   Figure 2. Survival curves of patients with SMZL according to the presence of losses assessed by CGH (0 versus 1 loss; P = 0.02).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Previous studies using conventional cytogenetics and fluorescence in situ hybridization have shown that interstitial deletion of the long arm of chromosome 7 is a recurrent cytogenetic abnormality in SMZL.^6,10,12,26 By CGH we have confirmed that partial loss of the 7q region is the most frequent loss in SMZL and the commonly deleted region is located at 7q31-q32. Recently, Corcoran and colleagues²⁷ found a deregulation of the CDK6 gene that could be involved in the pathogenesis of the small group of SMZL with translocations at 7q21. However, partial losses in 7q are more frequent than translocations in SMZL. These deletions of 7q are infrequent in other NHL^14,25,28,29 including marginal zone lymphomas.¹⁷ Moreover, studies by loss of heterozygosity have confirmed that 7q31-q32 loss is a relatively specific genetic marker of SMZL.¹¹ All of the cytogenetic, fluorescence in situ hybridization, loss of heterozygosity, and CGH data support the hypothesis that a loss in 7q31-q32 plays a key role in SMZL.

In our study, gains mostly involved 3q, 5q, 12q, and 20q. Chromosomal changes in 3q have been reported in several types of B-NHL. Half of the cases of mantle cell lymphoma have gains of 3q.^30,31 This incidence is lower in patients with diffuse large cell lymphoma (24%)¹⁵ or extranodal lymphoma (7 to 13%).^18,25 The reported overall incidence of gains of chromosome 3 in marginal zone lymphomas, including MALT (nodal and extranodal) and SMZL, is 52% and only two of the 11 cases of SMZL studied by Dierlamm and colleagues¹⁷ showed gains on 3q. In our series of 29 SMZL patients, the incidence was 31%. This frequency of imbalances on chromosome 3 is similar to that observed using fluorescence in situ hybridization.^6-9 It should be noted that, in contrast to other marginal cell lymphomas in which trisomy is the most frequent gain, using CGH we have observed that in SMZL the gain specifically occurs at the 3q arm.

In the present series, 28% of patients with SMZL had gains in chromosome 5q, with a consensus region in 5q13-q15. Gains of 5q have only been reported by CGH in NHL sporadically,^16,18,30,32 and in MALT lymphomas the incidence is 8%.¹⁷ Only one case of diffuse large cell lymphoma of the gastrointestinal tract has been described with an amplification of 5q33-q35.¹⁸ Moreover, by conventional cytogenetics abnormalities of 5q are also unusual in NHL and only two chromosome translocations, t(5;14)(q11;q32) and a t(5;7)(q13;q35) have been reported, in B and T NHL, respectively.³³ In 5q13, a gene involved in CDK-activating kinase complex of cyclin H MAT1³⁴ and in 5q31, a gene coding a phosphatase Cdc25 associated with regulation of cell cycle have both been recently located.³⁴ However, the possible relationship of these genes with SMZL still needs to be clarified. Although 5q13 abnormalities have not previously been related to SMZL, the region has been involved in hairy cell leukemia.^35,36 The demonstration in the present series of a high incidence of gains on 5q in SMZL, with a consensus region located at 5q13-q15, suggests that this region could be related to SMZL.

Using conventional cytogenetics, trisomy 12 or duplication 12q are frequently observed as a secondary genomic change in lymphoid disorders.^37,38 By contrast, in marginal lymphomas, abnormalities of chromosome 12 have rarely been reported.¹⁷ By CGH, numerical abnormalities of chromosome 12 have been detected in primary mediastinal B-cell lymphoma,³² primary gastrointestinal large-cell lymphoma,²⁵ and chronic lymphocytic leukemia.¹⁴ In our study, no cases with trisomy 12 were found. However we observed gains in the long arm of chromosome 12 in seven cases of SMZL with a consensus region in the bands 12q15-q21. In the long arm of chromosome 12 the region 12q24 has frequently been involved in mediastinal lymphomas³² and in primary large B-cell lymphoma of the gastrointestinal tract,¹⁸ whereas in mantle cell lymphomas, the consensus region was located at 12q13.³¹ In the region 12q13-q21 several genes such as GLI, MDM2, and CDK4 have been mapped. Amplification of these genes have been observed in diffuse large B-cell lymphoma, and associated with advanced state of disease.³⁹ Recently, our group has observed CDK4 gene amplifications in mantle cell lymphoma.³¹ However, their role in the pathogenesis of SMZL needs to be determined.

In the present study, gains of the long arm of chromosomes 9 and 20 were particularly frequent, 21 and 24%, respectively. Whereas changes observed in 9q have been reported in other lymphoma subtypes,^17,31 gains in 20q have been observed in only one case of mantle lymphoma.³⁰ Moreover, by conventional cytogenetics, the changes in this region are also uncommon in NHL.⁴⁰ However gains of 20q have been observed in solid tumors such as colorectal carcinoma,^41,42 breast,⁴³ bladder,⁴⁴ ovarian,⁴⁵ and pancreatic cancer.⁴⁶ Several candidate genes have been identified on 20q: the cellular apoptosis susceptibility (CAS) gene;⁴⁷ BTAK, a putative serine/threonine kinase gene;⁴⁸ AIB1, a steroid receptor co-activator gene;⁴⁹ PTPN1, a nonreceptor tyrosine phosphatase involved in growth regulation;⁵⁰ as well as MYB12, which encodes a transcription factor and plays an important role in cell cycle progression.⁵¹

Regarding gene amplifications, CGH studies are detecting an increased number of high-level DNA amplifications in lymphomas, which were relatively rare in NHL by cytogenetic studies.⁵² These results suggest that gene amplifications may be more frequent in NHL than initially thought.¹⁶ We found three high-level DNA amplifications in 29 SMZL involving 3q26-q29, 5p11-p15, and 17q22-q25. Amplifications of 3q26-q29 have been observed in NHL.^16,18,30,31 Abnormalities of 5p have been reported in B-cell disorders.^{17,18,31,32,39} However, to the best of our knowledge, no cases of NHL with high-level amplifications of 5p have been described. Amplifications in 17q23-25 have been previously reported in one case of mantle cell lymphoma.³¹ A relationship between high-level DNA amplifications and the location of chromosome fragile sites have been suggested.⁵³ In fact, the three amplified regions in SMZL were located in chromosomal regions where fragile sites have been identified. These data are according to the hypothesis that fragile sites may be implicated in the amplifications of certain chromosomal regions during tumor progression.⁵³ The ANCA index is a measure for the number of chromosomal copy alterations in a tumor. The correlation of the ANCA index with tumor progression may reflect the tumor aggressiveness.²³ The ANCA index of SMZL in the present series was 3.8 whereas this value ranged from 4.8 in the squamous cell carcinomas of the anal canal to the 8.3 in the high-grade astrocytomas.²³

Concerning the outcome, in the present series, we have observed that the presence of genetic losses was associated with a shorter survival than in other patients without deletions (36 versus 101 months). Little data about the impact of CGH on the outcome of the NHL are available. Recently, a relationship between the presence of more than four abnormalities by CGH or losses on 9p have been related to a poor outcome in mantle cell lymphoma.³¹ Our results suggest that in so-called indolent SMZL, two groups of patients based on CGH losses are present. Thus, patients with loss of chromosomal material in CGH showed a significantly poorer outcome as compared to patients without deletion or with few chromosomal changes, and therefore could be candidates for a more intensive therapeutic approach. Recently, Mateo and colleagues¹¹ associated the loss of 7q, assessed by loss of heterozygosity analysis, with a poor outcome.

In summary, the CGH data reported describes new regions related to SMZL (5q, 9q, 12q, and 20q). Although the high-level amplifications seem to be an uncommon mechanism in these lymphomas, three regions (3q26-q29, 5p11-p15, and 17q22-q25) were found to be amplified in SMZL. Moreover, our data confirmed that deletions of 7q31-q32 are closely associated with SMZL and showed that deletions in SMZL lead to a poor clinical outcome.

	Acknowledgements

 
We thank Pilar Fernández, M. Ángeles Hernández, Ana Simón, and Mark Anderson for the excellent technical assistance.

	Footnotes

 
Address reprint requests to Jesús M. Hernández Rivas, Servicio de Hematología, Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain. E-mail: jmhernandezr{at}aehh.org

Supported in part by grants of the Spanish Fondo de Investigaciones Sanitarias (98/1161; 98/0491, and 00/1089), and the Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Spain (to N. C. G.).

J. M. H. and J. L. G. contributed equally to the study and should both be considered as first authors.

Accepted for publication January 23, 2001.

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