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[Cancer Research 63, 2606-2609, May 15, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Allelic Losses on Chromosome 6q25 in Hodgkin and Reed Sternberg Cells1

Daniel Re, Petr Starostik, Nadia Massoudi, Andrea Staratschek-Jox, Volker Dries, Roman K. Thomas, Volker Diehl and Jürgen Wolf2

Department of Internal Medicine I [D. R., N. D., A. S-J., R. K. T., V. Di., J. W.] and Institute of Pathology [V. Dr.], University of Cologne, 50924 Cologne and Institute of Pathology [P. S.], University of Würzburg, 97080 Würzburg, Germany


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We established a molecular cytogenetic approach to identify consistent genetic aberrations in classical Hodgkin lymphoma. Single laser-micromanipulated Hodgkin and Reed Sternberg (H-RS) cells and the respective germ line tissue were PCR-amplified using highly polymorphic microsatellite probes. Loss of heterozygosity and genomic imbalances of the fluorochrome-labeled microsatellites were determined by fragment length analysis. Eleven cases of in classical Hodgkin lymphoma (cHL) were initially screened with 21 microsatellite markers scattered over the entire genome. Loss of heterozygosity was detected in >40% of informative loci in most cases indicating a deletion of a substantial part of the genome of H-RS cells. Allelic losses and imbalances on chromosome 6q were detected in most of these cases. A deletion mapping of 6q was performed in 16 cases of cHL. This detailed analysis of 6q led to the identification of a 3.3-Mbp region around D6S311 flanked by D6S978 and D6S1564 that was altered in 11 of 14 cases of cHL analyzed. In conclusion, allelotyping of single H-RS cells revealed monoallelic chromosomal deletions and genomic imbalances on 6q that might affect genes critically involved in the pathogenesis of H-RS cells.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
H-RS3 cells represent the malignant cells in classical Hodgkin lymphoma (cHL). These large multinuclear cells are characterized by their scarcity in the affected tissue. It was, therefore, only recently that single-cell studies disclosed the clonal germinal center B-cell derivation of H-RS cells in most instances (1, 2, 3) . Nevertheless, H-RS cells lack most of B-cell specific phenotypic and molecular markers (4, 5, 6) . One of the characteristic features of H-RS cells is the constitutive expression of NF{kappa}B (7) , which might explain apoptosis resistance of these cells. In a portion of cHL, NF{kappa}B expression may result from the expression of the EBV encoded latent membrane protein-1 (LMP-1) or from deleterious mutations of the NF{kappa}B repressor I{kappa}B{alpha} (8, 9, 10) . Mutations of genes involved in the pathogenesis of other B-cell lymphomas are rare or absent (11, 12, 13, 14) in H-RS cells.

H-RS cells display chromosomal instability as reflected by recurrent cytogenetic aberrations, but not microsatellite instability (15 , 16) . Despite the presence of grossly abnormal karyotypes in H-RS cells, no specific chromosomal aberration has been identified thus far in these cells because classic cytogenetic analyses are hampered by the scarcity and the low mitotic index of the H-RS cells (17, 18, 19) . Therefore, novel approaches like FISH or the combination of FISH and immunophenotyping have been applied to cHL. Results from these studies indicated (clonal) numerical or structural chromosomal aberrations in all cases of cHL (20 , 21) . More recently, H-RS cells were characterized by molecular cytogenetic methods like comparative genomic hybridization (22, 23, 24) or LOH (15 , 25 , 26) . These analyses indicated to the involvement of distinct genes in the pathogenesis of cHL (27 , 28) . Here we describe a high frequency of chromosomal deletions and imbalances in H-RS cells on 6q25 in 11 of 14 informative cases that might allow the identification of a novel chromosomal region possibly harboring tumor suppressor genes.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Pathological Specimens.
Pathologic specimens were classified according to the WHO classification (29) . Characteristics of these cases are given in Table 1Citation . From each sample, 5 x 105 cells were cytospun on a slide, air dried, and kryopreserved at -20°C. The corresponding H-RS cell-affected lymph nodes were kryopreserved in parallel. Peripheral blood samples were obtained at different time points. Cytospins were thawed at room temperature and stained with a monoclonal mouse antihuman CD30 antibody (clone Ber-H2; DAKO, Hamburg, Germany) and a secondary biotinylated rabbit antimouse antibody (clone E413, DAKO). Antibody reactions were detected with avidin-biotin-coupled alkaline phosphatase (DAKO) and FastRed as chromogen (DAKO). The EBV-negative H-RS cell line L1236 was established at our institution (30) .


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  		Table 1 Characteristics of cHL cases of 15 individuals and the H-RS cell line L1236

 
DNA Extraction.
High-molecular weight germ line DNA was extracted from H-RS cell-affected lymph nodes or from peripheral blood mononuclear cells of the respective patient according to standard procedures. Tumor DNA was obtained from pooled H-RS cells after micromanipulation without DNA extraction. Single multinuclear CD30 positive H-RS cells were isolated using a noncontact PALM Laser MicroBeam System (Bernried, Germany). Multiple cells were collected in a microfuge cap and transferred to PCR tubes containing PCR buffer (Promega) as described previously (1) .

PCR.
Multiplex-PCR was carried out for 10 pooled H-RS cells from primary cases. The first round amplification was performed in a 25-µl reaction volume containing 50 mM KCl, 2.5 mM MgCl2, 0.2 mM dNTPs, and a mixture of 21 primer pairs for screening experiments or a mixture of 7 primer pairs for mapping experiments (25 pmol of each). Microsatellites were chosen as suggested recently (31) . Oligonucleotide sequences were derived from the Genome Database4 and slightly modified. Internal nested oligonucleotides were designed using the respective DNA sequence and OLIGO software.5 Physical and cytogenetic positions of microsatellites are given in Table 2Citation . Forty cycles of denaturation (95°C for 30 min), annealing (57°C for 30 min), and elongation (72°C for 60 min) were performed in a personal cycler (Biometra, Göttingen, Germany) after adding 1 unit of Taq polymerase (Promega, Germany) during the first denaturation step. One microliter of the first PCR was reamplified in two separate reactions for each microsatellite as described before using 5'-labeled fluorescent oligonucleotides (6-carboxyfluorescein or hexachloro-6-carboxyfluorescein).


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  		Table 2 Physical position and cytogenetic localization of microsatellite markers

(A) 15 screening markers on 9 different chromosomes and (B) 13 mapping markers on chromosome 6q.

 
LOH Analysis.
An aliquot of the PCR amplificate was mixed with a 6-carboxy-X-rhodamine-labeled size standard and analyzed for fragment length on a 377 DNA sequencer (Applied Biosystems/Perkin-Elmer, Foster City, CA). GeneScan software was used for the analysis of microsatellites. Loci were scored informative if the germ line was heterozygous. Loci were scored not informative if the germ line was homozygous or if no PCR product was reproducibly obtained from one of the sources. Allelic imbalance was scored if the height ratio of one of the tumor alleles compared with the height ratio of the germ-line alleles was <60% or >140% (31) . LOH was scored only if one allele was completely absent.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
H-RS Cells Frequently Display Allelic Losses (LOH).
To avoid PCR amplification of incomplete chromosomal material, we used CD30-stained cytospins instead of lymph node sections for micromanipulation of H-RS cells (Fig. 1)Citation . In a first screening experiment, 10 cases of cHL and, in addition, the H-RS cell line L1236 were analyzed for LOH. Analysis of L1236 cells was possible because germ line tissue from the patient from whom the cell line was derived has been available for PCR analysis. Twenty-one microsatellite markers located on 9 different chromosomes were PCR-amplified from pooled H-RS cells, and the respective germ-line DNA. In five cases, H-RS cells were compared with both germ-line DNA from the H-RS cell-affected whole lymph node and DNA extracted from peripheral mononuclear cells from the respective patient. Because the microsatellite pattern did not differ between DNA extracted from the two sources (data not shown), we further on compared H-RS cell DNA solely with DNA obtained from lymph nodes.



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  		Fig. 1. Micromanipulation of single multinuclear CD30-positive H-RS cells from cytospins using a P.A.L.M. microscope (Bernried, Germany). Shown is a typical sequence during micromanipulation: identification of the H-RS cell, laser-ablation of bystanding cells, and isolation of the H-RS cell by a nontouch laser beam. The cell was transferred to a microfuge tube and used for multiplex PCR as described in "Material and Methods" (x 1000).

 
In 9 of these 11 cases, allelic losses were detected in at least 40% at informative loci, indicating a high degree of allelic losses in H-RS cells (see an example in Fig. 2Citation ). In the remaining two cases, LOH was detected in 0% and 13%, respectively (Table 3)Citation . The overall rate of complete allelic losses was 46%. Allelic imbalances were detected in 5% of analyzed microsatellite markers. In the 10 primary cases of cHL, complete allelic losses were scattered over nearly all chromosomes with a range from 0% (D18S1156) to 78% (D6S311), whereas H-RS cells of the cell line L1236 showed LOH on the long arm of chromosome 6 (6q). The microsatellite marker D6S311 on 6q25 displayed LOH in seven of nine informative cases (78%), including the cell line L1236. Deletions on 6q were confirmed by a second marker (D6S441) located telomeric of D6S311, which showed allelic losses in 60% of informative cases. Other markers showing frequently allelic losses include D2S391 (57%) and D3S1580 (67%) on chromosomes 2p23 and 3q26, respectively.



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  		Fig. 2. GeneScan analysis of microsatellite markers for detection of LOH. Alleles were labelled with a fluorescent dye during PCR and analyzed for allelic heterozygosity. A, example of a complete LOH in H-RS cells. Allelic pattern of D6S311 in a lymph node (identification no. 1507; above) and in pooled H-RS cells of that case (below) indicates a complete LOH for the 240-bp allele in the tumor cells. B, example of an genomic imbalance in H-RS cells. Comparison of D6S1599 alleles between the lymph node (identification no. 1494; above) and the respective micromanipulated pooled H-RS cells (below).

 

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  		Table 3 LOH analysis of pooled H-RS cells of 10 cHL cases and the H-RS cell line L1236

Results of a seminested multiplex PCR using 21 microsatellite markers are shown. Black filled boxes, complete LOH; black filled boxes with open circles, imbalances; gray filled boxes, no LOH; blank boxes, no PCR product. Identification numbers of cases correspond to Table 1Citation . LOH is calculated on the basis of informative markers. ni, not informative.

 
The methodological validity of this single-cell approach was tested by repeating several second-round PCRs for markers located on 6q. Thirty-three of 36 markers that could be amplified successfully showed an identical allelic pattern (92%). To show that both the seminested PCR strategy and the micromanipulation strategy represented robust methods, a second control experiment was performed. Single H-RS cells of case no. 1507 were micromanipulated in a second effort independently of the first experiment. Ninety-three percent of fragment-length analyses were identical.

Recurrent LOH on 6q25 in H-RS Cells.
A detailed deletion mapping of 6q was performed next using seven additional microsatellite markers around D6S311 and D6S441. Markers D6S977, D6S978, D6S1564, and D6S440 are located in the vicinity of D6S311, whereas the marker D6S1599 is close to D6S441. D6S1590 and D6S281 are located telomeric of D6S441 on 6q27. Using these seven 6q markers and the six 6q markers of the screening experiment, we analyzed five additional cHL cases for LOH on 6q. Thus, a total of 16 cHL cases (including the 10 cHL cases and the cell line L1236) were tested for LOH on 6q with 13 microsatellite markers.

Allelic losses of D6S311 on 6q25 detected in the screening experiment were found in two more cases of cHD out of five additional informative cases. The three remaining informative cases showed genetic imbalances at D6S311, thus not ruling out the possibility of incomplete allelic losses of this marker. In summary, 11 of 14 (79%) analyzed cases displayed genetic aberrations at D6S311. Markers D6S978 and D6S1564, which are located close to D6S311, showed allelic losses and imbalances in 57% and 50%, respectively. Allelic losses of D6S441 on 6q26 (60%) were confirmed by detection of monoallelic complete deletions of D6S1599 in 58% (7 of 12 informative cases). Results of deletion mapping are given in Fig. 3Citation . As observed before, complete allelic losses (41%) dominate over imbalances (16%).



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  		Fig. 3. 6q ideogram and results of allelotyping for detection of LOH in single-pooled H-RS cells. Cytogenetic position of microsatellite markers is indicated to scale according to GeneMap ’99 (www. ncbi.nlm.nih.gov/genemap99/) and the ensembl database (www.ensembl.org). Filled boxes, complete LOH; filled boxes with open circles, imbalances; hatched boxes, no LOH; open boxes, no PCR product. ni, not informative.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the cases analyzed in the presented study, H-RS cells lost an average of ~46% of their alleles, which is comparable with several solid tumors that have lost 25% to 50% of their alleles as they progressed (32) . The loci most frequently altered in our study were D6S311 and D6S441 on chromosome 6q followed by losses at D3S1580, D12S98, and D2S391 on chromosomes 3q, 12p, and 2p, respectively. Genetic aberrations were found to be highest at D6S311 on 6q25 in H-RS cells in 11 of 14 cHL cases. Although 6q aberrations are recurrent in 10% to 20% of cHL (19) , allelic losses and imbalances of a defined region on chromosome 6q in ~80% of cases have not been described. To our knowledge, no other genetic marker has been described to be altered in H-RS cells with a similar consistency.

In lymphomas, deletions of 6q were detected at a frequency of 7% to 42%, depending on the subtypes and the method applied (31 , 33, 34, 35, 36) . One report points toward a correlation between distinct lymphoma subtypes and specific deletions on 6q21, 6q23, and 6q25–27 (34) , but the specificity of these findings could not be confirmed in an independent FISH analysis (37) . Nevertheless, a tumor-suppressive potential of chromosomal regions on 6q, particularly on 6q25 has been shown in vitro and in vivo (38 , 39) . Tumor-suppressor genes like LATS-1 (40) or hZAC (41) located within this chromosomal region thus might play a role in the pathogenesis of several tumors and possibly also in cHL.

In H-RS cells, other microsatellite markers like D3S1580 and D2S391 are deleted recurrently as well. D2S391 displays LOH in 57% of informative cases and is located at 2p23.1. Several candidate tumor suppressor genes are located in the vicinity of that chromosomal region, including the mismatch repair gene hMSH2. This gene is of crucial importance for the correct functioning of the mismatch repair machinery. A defect of hMSH2 or other mismatch repair genes causes microsatellite instability and might contribute to malignant transformation of H-RS cells. In recent studies, however, microsatellite instability was not detected in pooled H-RS cells, and hMSH2 has been demonstrated to be expressed in cases of cHL (15 , 16) .

In this study, whole cells were isolated from cytospins (instead of frozen sections) and subsequently pooled to exclude loss of chromosomal material. Because most allelic losses were complete, genomic imbalance with amplification of the second allele could explain the microsatellite pattern detected in these cases. However, there are cases showing a pattern indicative of genomic imbalance. This imbalance might represent an incomplete allelic loss of one of the alleles or an amplification of the other allele. In these cases, incomplete losses may be explained by the presence of H-RS subclones lacking this particular allelic loss.

In summary, here we describe for the first time a recurrent aberration of a genetic marker in cHL, i.e., the microsatellite marker D6S311 located on chromosome 6q25, which is altered in ~80% of the cases analyzed. The indicated region on 6q harbors several tumor-suppressor genes that might be involved in the malignant transformation of H-RS cells.


   ACKNOWLEDGMENTS
 
We thank Julia Jesdinsky for excellent technical assistance and Karin Ernestus for latent membrane protein staining.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 502). Back

2 To whom requests for reprints should be addressed, at University of Cologne, Department of Internal Medicine I, Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany. Phone: 49-221-478-3410; Fax: 49-221-478-3744; E-mail: juergen.wolf{at}medizin.uni-koeln.de Back

3 The abbreviations used are: H-RS, Hodgkin and Reed Sternberg; FISH, fluorescence in situ hybridization; cHL, classical Hodgkin lymphoma; LOH, loss of Heterozygosity. Back

4 Internet address: www.gdb.org. Back

5 Internet address: www.oligo.net. Back

Received 3/30/03. Accepted 3/19/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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