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NEOPLASIA
From Deutsches Krebsforschungszentrum, Abteilung
Organisation komplexer Genome, Heidelberg, Germany; Abteilung für
Pathologie des Universitätsklinikums Ulm, Germany; Institut
für Humangenetik, Universitätsklinikum Kiel, Germany;
Pathologisches Institut der Universität Heidelberg, Germany; and
Abteilung Innere Medizin, Klinikum der Georg-August-Universität,
Göttingen, Germany.
Hodgkin- and Reed-Sternberg (HRS) cells microdissected from 41 classical Hodgkin lymphomas (cHL) of 40 patients comprising 8 lymphocyte-rich (cHL-LR), 16 nodular sclerosis (cHL-NS), 15 mixed-cellularity (cHL-MC), and 2 lymphocyte-depletion (cHL-LD) subtypes were analyzed by comparative genomic hybridization for recurrently imbalanced chromosomal subregions. Chromosomal gains most
frequently involved chromosome 2p (54%), 12q (37%), 17p (27%), 9p
and 16p (24% each), and 17q and 20q (20% each), whereas losses primarily affected chromosome 13q (22%). Using fluorescence in situ
hybridization, amplification of the REL oncogene was
demonstrated within a distinct 2p15-p16 amplicon. The high frequency of
2p overrepresentations including REL, particularly in
cHL-NS (88%), suggests that an alternative mechanism of constitutive
activation of nuclear factor NF- Hodgkin lymphoma (HL), which accounts for
approximately one third of all malignant lymphomas, is characterized by
the presence of only a small fraction of malignant cells. Neoplastic
cells represented as mononucleated Hodgkin- and multinucleated
Reed-Sternberg cells (HRS cells) are embedded in a varying infiltrate
of reactive cells including B and T lymphocytes, eosinophils, plasma
cells, and fibroblasts.1 According to the new World Health
Organization (WHO) classification,2 4 well-defined
histotypes of classical Hodgkin lymphoma (cHL) can be distinguished:
lymphocyte-rich (cHL-LR), nodular-sclerosis (cHL-NS), mixed-cellularity
(cHL-MC), and lymphocyte-depletion (cHL-LD). Paragranuloma (nodular
lymphocyte predominant Hodgkin lymphoma [NLPHL]) has been shown to be
clinically and immunophenotypically distinct and eventually to
transform to large B-cell non-Hodgkin lymphoma. This indicates that
NLPHL is essentially different from the cHL subtypes.
Because of the small number of malignant cells, cytogenetic analysis is
particularly difficult in HL and, to date, has not revealed any
specific chromosomal rearrangements. Detailed analysis by chromosome
banding is further limited by the low mitotic index of neoplastic
cells, frequently poor chromosome morphology, and complex karyotypic
rearrangements. For these reasons, it is difficult to obtain sufficient
numbers of karyotypes for evaluation that are representative of the
malignant cell population.3,4 Alternatively, combined
immunohistochemical and cytogenetic analyses by fluorescence in situ
hybridization (FISH) have been applied. It could be demonstrated that
chromosomal changes are almost exclusively restricted to CD30+ HRS cells. Furthermore, significant heterogeneity in
terms of the copy number of single chromosomes was detected using this approach.5-8
Recently, comparative genomic hybridization (CGH) was applied in
combination with universal polymerase chain reaction (PCR) technology
for cytogenetic analyses of HRS cells.9-11 These analyses indicated higher rates of numerical aberrations of individual chromosomes than had previously been found by banding analysis, in
which the identification of numerical changes is difficult because of
the complex karyotypes of HRS cells. Gains and losses in more than 50%
of the cHL tumors were identified on chromosomal arms 2p, 7q, and
16q,9,10 whereas in NLPHL, chromosomal arms 1q, 3p, 5q,
and Xq were affected.11 Although the number of analyses is
still low (20 cHLs and 20 NLPHLs to date), CGH has already allowed the
identification of several imbalanced chromosomal subregions, indicating
the localization of candidate genes that may be involved in the
etiology of this disease.
To further define critical subregions in cHL, a series of 41 tumors was analyzed (a small subset of cases was reported
recently10). To this end, collected pools of
approximately 30 malignant HRS cells from single tumors were isolated
using microdissection technology. Genomic DNA from the individual cell
pools was subsequently amplified by universal PCR technology and
analyzed by CGH. Hierarchical cluster analysis of the CGH data was
performed to assess particular patterns of chromosomal imbalances
associated with different histotypes of cHL.
Patients, lymphoma materials, and cell lines
HRS cell isolation
Degenerate-oligo-primed polymerase chain reaction HRS cells were digested with 10 to 20 units/mg proteinase K (250 µg/mL) in 20 µL of 1× PCR buffer (2 mM MgCl2, 50 mM KCl, 10 mM Tris, pH 8.3, 0.1 mg/mL gelatin) for 10 to 15 hours at 50°C, with subsequent inactivation of the enzyme at 94°C for 15 minutes. An additional aliquot of proteinase K was added and incubated for 3 hours at 37°C, during which time it was constantly shaken. After further inactivation of the enzyme, a DOP-PCR reaction was performed according to the protocol of Telenius et al.15Comparative genomic hybridization CGH was performed as previously described.16,17 Briefly, universally amplified genomic DNA from HRS cells was labeled with biotin by nick translation, after DOP primers had been removed using suitable columns. Because the control probe DNA isolated from peripheral blood lymphocytes or normal tonsils of healthy controls was differentially labeled with digoxigenin, 1 µg biotin-labeled tumor DNA, 1 µg digoxigenin-labeled control DNA, and 70 µg human Cot-1-DNA (BRL Life Sciences, Gaithersburg, MD) were cohybridized to slides with metaphase cells from the blood of a healthy donor. After hybridization, control and test DNAs were detected by rhodamine and fluorescein isothiocyanate (FITC), respectively. Images of 15 or fewer metaphase cells were recorded, and the ratio of FITC-rhodamine fluorescence intensities was calculated along each individual chromosome and averaged using dedicated software (CytoVision 3.52, Applied Imaging, Sunderland, United Kingdom; ISIS, Version 1.80, MetaSystems, Altlussheim, Germany). Ratio values of 1.25 and 0.75, which have been proven to provide robust criteria for diagnosing overrepresentation and underrepresentation, were used as upper and lower thresholds for the identification of chromosomal imbalances.18 Overrepresentations were considered high-level amplifications when the fluorescence ratio values exceeded 2.0 or when the FITC fluorescence showed strong focal signals and the corresponding ratio profile revealed an overrepresentation. Of the chromosomal regions recognized to be critical in CGH analyses, the centromeric regions, the Y chromosome, 1p32-p36, and chromosome 19 were not scored in the results for reasons specified elsewhere.19 The validity of the combined DOP-PCR-CGH approach was tested by several control experiments described below.Combined immunophenotyping and genotyping For combined immunophenotyping and genotyping of CD30+ HRS cells,20 frozen slides containing cryostat sections and imprints of primary cHLs were thawed, fixed for 10 minutes in acetone, and air dried. Immunostaining was performed using a CD30 monoclonal antibody (Dakopatts, Hamburg, Germany) followed by a detection cascade with AMCA-conjugated secondary antibodies. All steps were performed at room temperature with a 30-minute incubation period and subsequent washing. After fluorescence immunostaining, slides were incubated for 10 minutes in Carnoy fixative (methanol-acetic acid), washed in dH2O, and postfixed in 1% paraformaldehyde for 1 minute. Slides were then dehydrated through an ethanol series (70%, 85%, and 100%) and air-dried in the dark. FISH was performed with probes for centromere 2 (CEP-2 labeled with spectrum orange, Vysis) and pooled bacterial artificial chromosomes (BACs) 373L24 and 498O5 covering the REL oncogene (RZPD, Berlin, Germany). BACs were labeled with dUTP-spectrum green (Vysis) by random priming. Thirteen to 16 CD30+ HRS cells were evaluated in each tumor.Hierarchical cluster analysis To test for correlations between cytogenetic aberrations and clinical parameters including histologic cHL subtypes, age at tumor onset, and patient gender, a hierarchical cluster analysis of the CGH data was performed. Imbalances for 290 chromosomal subbands of all human metaphase chromosomes21 except 1p13-pter, 9q11,
16q11, 19, and Y (see above)were used for an uncentered complete
clustering. This was performed using the programs Cluster and TreeView,
developed by Eisen et al22 (http://rana.lbl.gov/).
Validity of combined DOP-PCR-CGH experiments The sensitivity and specificity of the combined PCR-CGH approach were determined by analyzing defined pools of cells from 2 cell lines, Colo 320 and MedB-1. Both lines had been thoroughly characterized by chromosome banding and FISH.12-14 Results of CGH analysis with genomic DNA that had not previously been subjected to DOP-PCR (conventional CGH) were compared with those obtained from combined PCR-CGH analysis of defined numbers of cells. Conventional CGH revealed 16 imbalances of chromosomal arms in cell line Colo 320 and 6 imbalances in MedB-1. With pools of 30 isolated cells, 12 of 16 imbalances were detected in Colo 320, and 5 of 6 imbalances were detected in MedB-1. With smaller cell populations, the sensitivity decreased as indicated in Table 1. No false-positive results were obtained in any of the groups under these conditions. Based on these results, all subsequent CGH analyses were performed, starting with approximately 30 cells. The reproducibility of this approach was demonstrated by independent analyses of 2 tumors (cHL-2 and cHL-33) in 2 of the laboratories involved in this study; both laboratories yielded identical results.
Analysis of HRS cells by combined DOP-PCR-CGH Pools of malignant HRS cells from 41 different cHL tumors were analyzed. Results are summarized in Figure 1 and Table 2. Imbalances were detected in all but 4 cHLs with an average number of 5 imbalances per tumor case (range, 0-16 imbalances). These included 158 gains (mean, 3.9 per tumor) and 46 losses (1.1 per tumor). Chromosomal losses most frequently affected chromosomal arms 13q (22%), Xp and Xq (12% each), and 1p, 4q and 17p (7% each). Overrepresentations were predominantly found on chromosomal arms 2p in 54%, on 12q in 37%, and on 17p in 27% of cases. Lower frequencies (less than 25%) were detected for 9p and 16p (24% each), 17q and 20q (20% each), and 9q, 22q and Xq (17% each). Detailed chromosomal subregions involved are indicated in Table 2. Distinct amplifications were found in 7 different tumors and involved chromosomal bands 2p14-p16, 3q21, 4p16, 4q23-q24, 5p15, 5p11-p13, and 12q13-q14.
Among the cHL subtypes, there were numerical differences in chromosomal
aberrations. The average number of imbalances was highest in cHL-MC, as
indicated for selected chromosomes shown in Table
3. Gains of chromosomal arm 2p were
highly characteristic for cHL-NS (88% of cases) but occurred less
frequently in cHL-MC (47% of cases) and cHL-LR (13% of cases).
Hierarchical cluster analysis To identify possible genotype-phenotype relationships, hierarchical cluster analysis based on CGH data was performed. Only tumors in which chromosomal imbalances had been identified were included in this analysis.Figure 2 shows the resultant dendrogram
of the clustered tumor cases. Pairs of tumors with the highest degree
of similarity are connected and linked with further similar cases
resulting in the generation of higher order clusters, with short or
long "branches" indicating a higher or lower degree of similarity, respectively. Comparing the tumors in clusters C1 to C4, indicated in
Figure 2, revealed a nonrandom distribution of cHL subtypes: 11 of 16 cHL-NS cases were attributed to a single cluster (C1), whereas 4 of 6 cHL-LR subtypes appeared in cluster C4. cHL-MC tumors were found
distributed in clusters C2 to C4. This indicates a strong association
of most of the cHL-NS tumors, with a pattern of chromosomal imbalances
that is distinct from that in cHL-MC and cHL-LR.
The variously clustered patterns were also correlated with age at time of diagnosis. Thus, patients in clusters C1 and C2 were younger than those in C3 and C4 (Figure 2). The cluster containing the youngest patients was C2 (mean age, 27 years). In addition, this cluster was predominantly composed of tumors of the cHL-MC subtype and frequently showed overrepresentation of 17p. This is indicative of a possible correlation of 17p gains with early tumor onset within a subgroup of cHL-MC. Concerning the distribution of sexes in the 4 clusters, there was a predominance of female patients in clusters C1 and C3 (female-to-male ratio, 1.8 and 2.0, respectively), whereas in C2 and C4 an almost equal ratio was observed (female-to-male ratio, 1.3 and 1.0, respectively). C1 and C3 are largely composed of cHL-NS tumors, reflecting the predominance of females in this subtype.23 Analysis of increased copy number of REL In 3 cHL tumors, in which CGH detected a chromosome 2p gain (cHL-24, cHL-31, and cHL-33), the copy number of the REL oncogene located within 2p14-p15 could be determined. This was performed by combined immunophenotyping and genotyping analysis of CD30+ HRS cells without prior knowledge of the CGH results. BAC clones spanning the complete REL gene were used in addition to a differentially labeled control probe specific for the chromosome 2 centromere. Consistent with CGH, cHL-31 showed increased copy numbers of the centromeric region and the REL locus (median, 5 copies each). Case cHL-33 displayed a median of 4 copies of the chromosome 2 centromeric region and a median of 6 copies of the REL gene, also coinciding well with the CGH results (Figure 1). The signal pattern in this case suggested duplication within chromosomal arm 2p. In cHL-24, which according to CGH exhibits a distinct high-level amplification of chromosomal band 2p15-p16, a median number of 3 centromere-2 signals versus 9 REL signals was observed (Figure 3). This demonstrates that the REL locus is included within the distinct 2p15-p16 amplicon, which constitutes the consensus region of 2p gains detected in cHLs by CGH.
In the current study we show that chromosomal imbalances can be detected with high sensitivity and specificity in pools of 30 microdissected cells. The potential of this combined DOP-PCR-CGH method has been demonstrated by several groups, though larger pools of cells were analyzed in most studies.9-11,24-29 The application of this powerful approach for the analysis of enriched HRS cells in cHL revealed highly characteristic chromosomal imbalances. The most typical change was an overrepresentation of chromosomal arm 2p, which was observed in approximately half of all cases analyzed and in 88% of the cHL-NS subtype. Such a characteristic abnormality has not been observed in previous chromosome banding studies. Our analysis also indicated distinct patterns of cytogenetic aberrations associated with different cHL subtypes. Finally, evidence was provided to show that the classical type of Hodgkin lymphoma clearly differs from NLPHL.11 None of the chromosomes most frequently imbalanced in NLPHL (eg, gains of 1q, 3p, 5q, and Xq and losses of 11q and 17p) was affected in cHL. On the other hand, only a few of the imbalances typically found in cHL (eg, 2p, 9p, and 13q) were observed in NLPHL. Hence, Hodgkin lymphoma cannot be subdivided based only on morphologic and immunologic parameters,23 it can be subdivided based on the genomic level. To date, chromosome-banding analysis has contributed most information about cytogenetic aberrations in HRS cells. Among a number of nonrandom changes associated with HL, additional copies of chromosomes 2, 5, 9, and 12 were observed by several groups in up to 46% of cases.30-35 However, a wide range of other chromosomes was found to be affected by numerical changes, and the significance of individual aberrations was thus difficult to estimate. By measuring net chromosomal gains and losses in pools of HRS cells, a more specific pattern of recurrent chromosomal imbalances was detected that involved relatively few chromosomal arms or subregions (eg, 2p15-p16, 9p23-p24, 12q24, 13q14-q21, 16p and 17). Therefore, CGH results point to the localization of genes that might be critical for the etiology of cHL. Gains of chromosome 2p, the most frequent aberration found in 54%
of cHL cases, were only detected recurrently in diffuse large B-cell
lymphoma and mediastinal B cell lymphoma (23% and 22%,
respectively).17,36,37 This high frequency points to a
gene important for cHL pathogenesis. The consensus region of chromosome
2p gains involved band 2p15-p16, which corresponds to the mapping
position of the REL oncogene.38 Gains and
high-level amplifications of this gene were also found in approximately
80% of cHL tumors by combined immunophenotyping and interphase
cytogenetics (see accompanying article by Martín-Subero et
al,39 page 1474). REL codes for a
subunit of NF- Gains of chromosomal arm 9p were detected in 24% of cHLs. The smallest
overrepresented regions included 9p11-p12 and 9p24. Interesting
candidate genes within these chromosomal bands are the NF1B
gene encoding for a transcription factor and the tyrosine kinase gene
JAK2, both of which are located on 9p24. JAK2 is
involved in signal transduction of cytokine receptors48,49
and was recently shown to be amplified in the HL-derived line HDLM-2
and in one case of NLPHL.10 Interestingly, both the
JAK/STAT system and the NF- In HRS cells, 9p gains were detected in 25% of cHL tumors. The frequency of this aberration is topped by mediastinal B-cell lymphoma (MBL), in which 9p gains were detected by CGH in more than 50% of tumors. In contrast, in all other B-NHLs tested so far, cases with 9p gains account for just 2%.14 Both, cHL and MBL also exhibit frequent gains of chromosomal arm 2p, including the REL oncogene.14,37 These parallels support a recent hypothesis suggesting a pathogenic relationship between these 2 types of lymphoma. This hypothesis arose from the observation of rare cases of cHL-MBL of composite lymphomas.52 In addition, both share a number of clinical and immunologic features, including their frequent mediastinal origin and the lack of functional expression of HLA class I and immunoglobulin molecules.53-55 Concerning chromosomal region 12q24, further candidates include BCL7A56 and the gene for the HRS-specific intermediate filament, restin,57 whereas chromosome 16p13 harbors cyclin F.58 The RB1 gene is located within the recurrently deleted region 13q13-q21, and there is strong evidence of further tumor suppressor genes residing within this region.59-61 Facing the complexity of chromosomal imbalances we found in HRS cells, hierarchical cluster analysis was carried out to eventually detect genotype-phenotype relations. Four clusters emerged. Cluster C1 was predominantly attributed to cHL-NS. Clusters C2 and C4 were predominantly attributed to cHL-MC. Cluster C4 also comprised most of cHL-LR. Cluster C3 did not appear to be related to cHL subtypes. The different clustering of cHL subtypes suggests nonrandom combinations of chromosomal imbalances. First, cHL-NS showed a particularly high frequency of 2p gains. Second, the major features of differences between cHL-MC clustering in C2 and C4 were age of onset and 17p+. Overrepresentation of 17p in cHL-MC was more frequent in younger patients than in older patients. These results have now to be confirmed in an independent cohort of cHL tumors. However, the different emerging clusters argue for different routes of pathogenesis in cHL, with 2p gains as an early event or a common feature.
We thank Axel Benner (DKFZ, Heidelberg) for discussion of statistical analysis, Iwona Nerbas for excellent technical assistance, and Caroline Higginson for editorial help.
Submitted July 12, 2001; accepted October 10, 2001.
Supported by the Tumorzentrum Heidelberg/Mannheim (I.I.2), the Deutsche Krebshilfe (70-2310-Ba), and the IZKF Kiel.
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: Peter Möller, Abteilung für Pathologie, Universität Ulm, Albert- Einstein-Allee 11, D-89081 Ulm, Germany; e-mail: peter.moeller{at}medizin.uni-ulm.de.
1. Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF. Classic Hodgkin's disease. In: Rosai J,Sobin LH, eds. Tumors of the Lymph Nodes and Spleen. Vol 14. Washington, DC: Armed Forces Institute of Pathology; 1995:43-62. 2. Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues. Lyons, France: IARC Press; 2001. 3. Rowley JD. Chromosomes in Hodgkin's disease. Cancer Treat Rep. 1982;66:639[Medline] [Order article via Infotrieve]. 4. Atkin NB. Cytogenetics of Hodgkin's disease. Cytogenet Cell Genet. 1998;80:23-27[CrossRef][Medline] [Order article via Infotrieve]. 5. Teerenhovi L, Lindholm L, Pakkala A, Franssila K, Stein H, Knuutila S. Unique display of a pathologic karyotype in Hodgkin's disease by Reed-Sternberg cells. Cancer Genet Cytogenet. 1988;34:304-311.
6.
Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegelberger B.
Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg Cells in 100% of analyzed cases of Hodgkin's disease.
Blood.
1995;86:1464-1468
7.
Pringle JH, Shaw JA, Gillies A, Lauder I.
Numerical chromosomal aberrations in Hodgkin's disease detected by in situ hybridization on routine paraffin sections.
J Clin Pathol.
1997;50:553-558 8. Jansen MPHM, Hopman AHN, Haesevoets AM, et al. Chromosomal abnormalities in Hodgkin's disease are not restricted to Hodgkin/Reed-Sternberg cells. J Pathol. 1998;185:145-152[CrossRef][Medline] [Order article via Infotrieve]. 9. Ohshima K, Ishiguro M, Ohgami A. Genetic analysis of sorted Hodgkin and Reed-Sternberg cells using comparative genomic hybridization. Int J Cancer. 1999;82:250-255[CrossRef][Medline] [Order article via Infotrieve].
10.
Joos S, Küpper M, Ohl S, et al.
Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells.
Cancer Res.
2000;60:549-552
11.
Franke S, Wlodarska I, Maes B, et al.
Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances.
Blood.
2001;97:1845-1853
12.
Quinn LA, Moore GE, Morgan RT, Woods LK.
Cell lines from human colon carcinoma with unusual cell products, double minutes and homogeneously staining regions.
Cancer Res.
1979;39:4914-4924 13. Nacheva EP, Grace CD, Bittner M, Ledbetter DH, Jenkins RB, Green AR. Comparative genomic hybridization: a comparison with molecular and cytogenetic analysis. Cancer Genet Cytogenet. 1998;100:93-105[CrossRef][Medline] [Order article via Infotrieve]. 14. Bentz M, Barth TF, Brüderlein S, et al. Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line. Genes Chromosomes Cancer. 2001;30:393-401[CrossRef][Medline] [Order article via Infotrieve]. 15. Telenius H, Pelmear A, Tunnacliffe A, et al. Cytogenetic analysis by chromosome painting using DOP-PCR amplified flow-sorted chromosomes. Genes Chromosome Cancer. 1992;4:257-263[Medline] [Order article via Infotrieve]. 16. Lichter P, Bentz M, du Manoir S, Joos S. In: Verma RS, Babu A, eds. Comparative Genomic Hybridization. New York, NY: McGraw-Hill; 1995:191-210.
17.
Barth TF, Döhner H, Werner CA, et al.
Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastrointestinal tract.
Blood.
1998;91:4321-4330 18. Barth TF, Benner A, Bentz M, Döhner H, Möller P, Lichter P. Risk of false positive results in comparative genomic hybridization. Genes Chromosomes Cancer. 2000;28:353-357[CrossRef][Medline] [Order article via Infotrieve].
19.
Solinas-Toldo S, Wallrapp C, Müller-Pillasch F, Bentz M, Gress T, Lichter P.
Mapping of chromosomal imbalances in pancreatic carcinoma by comparative genomic hybridization.
Cancer Res.
1996;56:3803-3807 20. Schlegelberger BMS, Harder S, Zühlke-Jenisch R, Zhang Y, Siebert R. In: Wegner RD, ed. Classical and molecular cytogenetics of tumor cells. Berlin, Germany: Springer-Verlag; 1999:151-185. 21. ISCN. 1995: An international system for human cytogenetic nomenclature. Farmington, CT: S Karger Publishers; 1995.
22.
Eisen MB, Spellman PT, Brown PO, Botstein D.
Cluster analysis and display of genome-wide expression patterns.
Proc Natl Acad Sci U S A.
1998;95:14863-14868
23.
Harris NL, Jaffe ES, Stein H, et al.
A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group.
Blood.
1994;84:1361-1392
24.
Speicher MR, du Manoir S, Schröck E, et al.
Molecular cytogenetic analysis of formalin-fixed, paraffin-embedded solid tumors by comparative genomic hybridization after universal DNA-amplification.
Hum Mol Genet.
1993;2:1907-1914 25. Speicher MR, Jauch A, Walt H, et al. Correlation of microscopic phenotype with genotype in a formalin-fixed, paraffin-embedded testicular germ cell tumor with universal DNA amplification, comparative genomic hybridization, and interphase cytogenetics. Am J Pathol. 1995;146:1332-1340[Abstract]. 26. Schütz BR, Scheurlen W, Krauss J, et al. Mapping of chromosomal gains and losses in primitive neuroectodermal tumors by comparative genomic hybridization. Genes Chromosome Cancer. 1996;16:196-203[CrossRef][Medline] [Order article via Infotrieve]. 27. Kuukasjärvi T, Tanner M, Pennanen S, Karhu R, Visakorpi T, Isola J. Optimizing DOP-PCR for universal amplification of small samples in comparative genomic hybridization. Genes Chromosome Cancer. 1997;18:94-101[CrossRef][Medline] [Order article via Infotrieve].
28.
Weber RG, Boström J, Wolter M, et al.
Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression.
Proc Natl Acad Sci U S A.
1997;94:14719-14724
29.
Weber RG, Scheer M, Born A, et al.
Recurrent chromosomal imbalances detected in biopsy material from oral premalignant and malignant lesions by combined tissue microdissection, universal DNA amplification, and comparative genomic hybridization.
Am J Pathol.
1998;153:295-303 30. Thangavelu M, Le Beau M. Chromosomal abnormalities in Hodgkin's disease. Hematol/Oncol Clin North Am. 1989;3:221-236[Medline] [Order article via Infotrieve]. 31. Döhner H, Bloomfield CD, Frizzera G, Frestedt J, Arthur DC. Recurring chromosome abnormalities in Hodgkin's disease. Genes Chromosome Cancer. 1992;5:392-398[Medline] [Order article via Infotrieve]. 32. Schlegelberger B, Weber-Matthisen K, Himmler A, et al. Cytogenetic findings and results of combined immunophenotyping and karyotyping in Hodgkin's disease. Leukemia. 1994;8:72-80[Medline] [Order article via Infotrieve].
33.
Schouten HC, Sanger WG, Duggam M, Weisenburger DD, MacLennan KA, Armitage JO.
Chromosomal abnormalities in Hodgkin's disease.
Blood.
1989;73:2149-2154
34.
Tilly H, Bastard C, Delastre T, et al.
Cytogenetic studies in untreated Hodgkin's disease.
Blood.
1991;77:1298-1304 35. Pedersen RK, Sorensen AG, Pedersen NT, Schmidt KG, Kerndrup GB. Chromosome aberrations in adult Hodgkin disease in a Danish population-based study. Cancer Genet Cytogenet. 1999;110:128-132[CrossRef][Medline] [Order article via Infotrieve].
36.
Houldsworth D, Mathew S, Rao PH, et al.
Rel proto-oncogene is frequently amplified in extra-nodal diffuse large cell lymphoma.
Blood.
1996;87:25-29
37.
Joos S, Otaño-Joos MI, Ziegler S, et al.
Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene.
Blood.
1996;87:1571-1578 38. Mathew S, Murty VVVS, Dalla-Favera R, Chaganti RSK. Chromosomal localization of genes encoding the transcription factors, c-rel, NF-kBp50, NF-kBp65 and lyt-10 by fluorescence in situ hybridization. Oncogene. 1993;8:191-193[Medline] [Order article via Infotrieve].
39.
Martín-Subero JI, Gesk S, Harder L, et al.
Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma.
Blood.
2002;99:1474-1477 40. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-653[CrossRef][Medline] [Order article via Infotrieve]. 41. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405-455[CrossRef]. 42. Wulczyn FG, Krappmann D, Scheidereit C. The NF-kappa B/Rel and I kappa B gene families: mediators of immune response and inflammation. J Mol Med. 1996;74:749-769[CrossRef][Medline] [Order article via Infotrieve]. 43. Rayet B, Gelinas C. Aberrant REL/NFKB genes and activity in human cancer. Oncogene. 1999;18:6938-6947[CrossRef][Medline] [Order article via Infotrieve].
44.
Bargou R, Emmerich F, Krappmann D, et al.
Constitutive nuclear factor-
45.
Wood KM, Roff M, Hay RT.
Defective I
46.
Jungnickel B, Staratschek-Jox A, Brauninger A, et al.
Clonal deleterious mutations in the I
47.
Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dörken B, Scheidereit C.
Molecular mechanisms of constitutive NF- 48. Ihle JN, Kerr IA. JAKs and STATs in signaling by the cytokine receptor superfamily. Trends Genet. 1995;11:69-74[CrossRef][Medline] [Order article via Infotrieve]. 49. Leaman DW, Leung S, Li X, Stark GR. Regulation of STAT-dependent pathways by growth factors and cytokines. FASEB J. 1996;10:1578-1588[Abstract].
50.
Ohmori Y, Schreiber RD, Hamilton TA.
Synergy between interferon- 51. Stephanou A, Latchman DS. Transcriptional regulation of the heat shock protein genes by STAT family transcription factors. Gene Expr. 1999;7:311-319[Medline] [Order article via Infotrieve]. 52. Rüdiger T, Jaffe E, Delsol G, et al. Workshop report on Hodgkin's disease and related diseases ('grey zone' lymphoma). Ann Oncol. 1998;(suppl 5):31-38. 53. Stein H, Gerdes J, Schwab U, et al. Identification of Hodgkin and Sternberg-Reed cells as a unique cell type derived from a newly-detected small-cell population. Int J Cancer. 1982;30:445-459[Medline] [Order article via Infotrieve].
54.
Möller P, Moldenhauer G, Momburg F, et al.
Mediastinal lymphoma of clear cell type is a tumor corresponding to terminal steps of B cell differentiation.
Blood.
1987;69:1087-1095 55. Ruprai A, Pringle J, Angel C, Kind C, Lauder I. Localization of immunoglobulin light chain mRNA expression in Hodgkin's disease by in situ hybridization. J Pathol. 1991;164:37-40[CrossRef][Medline] [Order article via Infotrieve].
56.
Zani VJ, Asou N, Jadayel D, et al.
Molecular cloning of a complex chromosomal translocation t(8;14,12)(q24.1;q32;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon.
Blood.
1996;87:3124-3134
57.
Delabie J, Shipman R, Bruggen J, et al.
Expression of the novel intermediate filament-associated protein restin in Hodgkin's disease and anaplastic large-cell lymphoma.
Blood.
1992;80:2891-2896 58. Prosperi E, Stivala LA, Scovassi AI, Bianchi L. Cyclins: relevance of subcellular localization in cell cycle control. Eur J Histochem. 1997;41:161-168[Medline] [Order article via Infotrieve]. 59. Liu Y, Corcoran M, Rasool O, et al. Cloning of two candidate tumor suppressor genes within a 10-kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia. Oncogene. 1997;15:2463-2473[CrossRef][Medline] [Order article via Infotrieve]. 60. Kapanadze B, Kashuba V, Baranova A, et al. A cosmid and cDNA fine physical map of a human chromosome 13q14 region frequently lost in B-cell chronic lymphocytic leukemia and identification of a new putative tumor suppressor gene, Leu5. FEBS Lett. 1998;426:266-270[CrossRef][Medline] [Order article via Infotrieve]. 61. Stilgenbauer S, Nickolenko J, Wilhelm J, et al. Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene. 1998;16:1891-1897[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  S. Hartmann, J. I. Martin-Subero, S. Gesk, J. Husken, M. Giefing, I. Nagel, J. Riemke, A. Chott, W. Klapper, M. Parrens, et al. Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization Haematologica, September 1, 2008; 93(9): 1318 - 1326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liu, S. Ranka, and T. Kahveci Classification and feature selection algorithms for multi-class CGH data Bioinformatics, July 1, 2008; 24(13): i86 - i95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Feys, B. Poppe, K. De Preter, N. Van Roy, B. Verhasselt, P. De Paepe, A. De Paepe, and F. Speleman A detailed inventory of DNA copy number alterations in four commonly used Hodgkin's lymphoma cell lines Haematologica, July 1, 2007; 92(7): 913 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Jost and J. Ruland Aberrant NF-{kappa}B signaling in lymphoma: mechanisms, consequences, and therapeutic implications Blood, April 1, 2007; 109(7): 2700 - 2707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, S. Ranka, and T. Kahveci Markers improve clustering of CGH data Bioinformatics, February 15, 2007; 23(4): 450 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Pfeifer, M. Pantic, I. Skatulla, J. Rawluk, C. Kreutz, U. M. Martens, P. Fisch, J. Timmer, and H. Veelken Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays Blood, February 1, 2007; 109(3): 1202 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Martin-Subero, W. Klapper, A. Sotnikova, E. Callet-Bauchu, L. Harder, C. Bastard, R. Schmitz, S. Grohmann, J. Hoppner, J. Riemke, et al. Chromosomal Breakpoints Affecting Immunoglobulin Loci Are Recurrent in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin Lymphoma Cancer Res., November 1, 2006; 66(21): 10332 - 10338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, J. Mohammed, J. Carter, S. Ranka, T. Kahveci, and M. Baudis Distance-based clustering of CGH data Bioinformatics, August 15, 2006; 22(16): 1971 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Renne, J. I. Martin-Subero, M. Eickernjager, M.-L. Hansmann, R. Kuppers, R. Siebert, and A. Brauninger Aberrant Expression of ID2, a Suppressor of B-Cell-Specific Gene Expression, in Hodgkin's Lymphoma Am. J. Pathol., August 1, 2006; 169(2): 655 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dijkman, C. P. Tensen, E. S. Jordanova, J. Knijnenburg, J. J. Hoefnagel, A. A. Mulder, C. Rosenberg, A. K. Raap, R. Willemze, K. Szuhai, et al. Array-Based Comparative Genomic Hybridization Analysis Reveals Recurrent Chromosomal Alterations and Prognostic Parameters in Primary Cutaneous Large B-Cell Lymphoma J. Clin. Oncol., January 10, 2006; 24(2): 296 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kasugai, H. Tagawa, Y. Kameoka, Y. Morishima, S. Nakamura, and M. Seto Identification of CCND3 and BYSL as Candidate Targets for the 6p21 Amplification in Diffuse Large B-Cell Lymphoma Clin. Cancer Res., December 1, 2005; 11(23): 8265 - 8272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hachem and R. B. Gartenhaus Oncogenes as molecular targets in lymphoma Blood, September 15, 2005; 106(6): 1911 - 1923. [Full Text] [PDF]
|
|
|
|
|
|
D. Re, R. K. Thomas, K. Behringer, and V. Diehl From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential Blood, June 15, 2005; 105(12): 4553 - 4560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Renne, K. Willenbrock, R. Kuppers, M.-L. Hansmann, and A. Brauninger Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma Blood, May 15, 2005; 105(10): 4051 - 4059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vandesompele, M. Baudis, K. De Preter, N. Van Roy, P. Ambros, N. Bown, C. Brinkschmidt, H. Christiansen, V. Combaret, M. Lastowska, et al. Unequivocal Delineation of Clinicogenetic Subgroups and Development of a New Model for Improved Outcome Prediction in Neuroblastoma J. Clin. Oncol., April 1, 2005; 23(10): 2280 - 2299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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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|
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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]
|
|
|
|
|
|
D. Re, P. Starostik, N. Massoudi, A. Staratschek-Jox, V. Dries, R. K. Thomas, V. Diehl, and J. Wolf Allelic Losses on Chromosome 6q25 in Hodgkin and Reed Sternberg Cells Cancer Res., May 15, 2003; 63(10): 2606 - 2609. [Abstract] [Full Text] [PDF]
|
|
|
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|
|
T. F. E. Barth, J. I. Martin-Subero, S. Joos, C. K. Menz, C. Hasel, G. Mechtersheimer, R. M. Parwaresch, P. Lichter, R. Siebert, and P. Moller Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma Blood, May 1, 2003; 101(9): 3681 - 3686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Martinez-Climent, A. A. Alizadeh, R. Segraves, D. Blesa, F. Rubio-Moscardo, D. G. Albertson, J. Garcia-Conde, M. J. S. Dyer, R. Levy, D. Pinkel, et al. Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations Blood, April 15, 2003; 101(8): 3109 - 3117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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M. Nishikori, Y. Maesako, C. Ueda, M. Kurata, T. Uchiyama, and H. Ohno High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease Blood, April 1, 2003; 101(7): 2789 - 2796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
E. M. Maggio, A. van den Berg, D. de Jong, A. Diepstra, and S. Poppema Low Frequency of FAS Mutations in Reed-Sternberg Cells of Hodgkin's Lymphoma Am. J. Pathol., January 1, 2003; 162(1): 29 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Franke, I. Wlodarska, B. Maes, P. Vandenberghe, R. Achten, A. Hagemeijer, and C. De Wolf-Peeters Comparative Genomic Hybridization Pattern Distinguishes T-Cell/Histiocyte-Rich B-Cell Lymphoma from Nodular Lymphocyte Predominance Hodgkin's Lymphoma Am. J. Pathol., November 1, 2002; 161(5): 1861 - 1867. [Abstract] [Full Text] [PDF]
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J. I. Martin-Subero, S. Gesk, L. Harder, T. Sonoki, P. W. Tucker, B. Schlegelberger, W. Grote, F. J. Novo, M. J. Calasanz, M. L. Hansmann, et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma Blood, February 15, 2002; 99(4): 1474 - 1477. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
B is a hallmark of HRS cells.
Hierarchical cluster analysis of chromosomal imbalances revealed a
closer relationship among cHL-NS than other subtypes. Furthermore,
there is a tendency for different subtypes of cHL-MC tumors
characterized by different ages at the time of tumor onset and gain of
chromosome 17p. The imbalance pattern of cHL subtypes suggests that
different molecular pathways are activated, with REL or
other genes on chromosomal band 2p15-p16 playing a fundamental role in
the pathogenesis of classical Hodgkin lymphoma.
(Blood. 2002;99:1381-1387)
in Hodgkin cell lines with constitutively active NF-
and tumor necrosis factor-