|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.02.0842 on December 5 2005 © 2006 American Society of Clinical Oncology. Array-Based Comparative Genomic Hybridization Analysis Reveals Recurrent Chromosomal Alterations and Prognostic Parameters in Primary Cutaneous Large B-Cell LymphomaFrom the Departments of Dermatology, Molecular Cell Biology, and Pathology, Leiden University Medical Center, Leiden, the Netherlands Address reprint requests to C.P. Tensen, PhD, Department of Dermatology, Leiden University Medical Center, Sylvius Bldg, Wassenaarseweg 72, 2333 AL Leiden, the Netherlands; e-mail: C.P.Tensen{at}lumc.nl
PURPOSE: To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). PATIENTS AND METHODS: Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. RESULTS: The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. CONCLUSION: Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.
In the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification, primary cutaneous B-cell lymphoma (CBCL) with the histology of a diffuse large B-cell lymphoma are classified as either primary cutaneous follicle center lymphoma (PCFCL) or primary cutaneous large B-cell lymphoma, leg type (PCLBCL, leg type).1 PCFCL generally presents with skin lesions confined to a limited area on the head or the trunk, rarely disseminate to extracutaneous sites, and has an excellent prognosis (5-year survival > 95%).1-4 Histologically, these PCFCLs represent a spectrum with variable proportions of (small) centrocytes and centroblasts and sometimes a follicular growth pattern in early lesions to diffuse infiltrates of generally large centrocytes (large cleaved cells) in tumorous lesions.2,4-7 The neoplastic B-cells consistently express BCL-6, but generally not BCL-2 and MUM1/IRF4.5,8-11
In the EORTC classification, PCLBCL of the leg was included as a separate entity, histologically characterized by confluent sheets of centroblasts and immunoblasts and, in contrast to the group of PCFCL, strong expression of BCL-2 and MUM1 proteins.3,9,10,12,13 Characteristically, these lymphomas present with skin tumors on the (lower) legs in elderly patients. As compared to the group of PCFCLs, these lymphomas more frequently disseminate to extracutaneous sites and have a poorer prognosis (5-year survival Recent studies have started to evaluate the genetic mechanisms involved in the development and progression of these lymphomas. Gene expression profiling suggested that PCFCL and PCLBCL, leg type, have gene expression profiles similar to that of germinal center B-cell–like and activated B-cell–like diffuse large B-cell lymphoma, respectively, and revealed MUM1 expression as a valuable diagnostic marker for the latter group.10 Previous studies using classical comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) demonstrated a higher number of chromosomal aberrations in PCLBCL, leg type, compared with PCFCL and demonstrated that translocations involving c-MYC, BCL6, and IgH genes are found only in PCLBCL, leg type.14,15 Taken together, these studies provided further support for the view that PCFCL with a diffuse infiltration of large centrocytes and PCLBCL, leg type, are distinct types of CBCL. However, they did not provide parameters allowing differentiation between PCLBCL, leg type, with a good or poor prognosis. In the present study, 19 biopsy samples of PCFCL and 12 of PCLBCL, leg type, were investigated for chromosomal aberrations using an array-based CGH. As compared with classical CGH, genomic DNA-chip hybridization provides a comprehensive, genome-wide analysis at a high spatial resolution. The aim of this study was to further define chromosomal aberrations in PCFCL and PCLBCL, leg type, and in particular to find differences between PCLBCL, leg type, with a favorable and unfavorable prognosis. The results of this study show clear-cut differences in chromosomal aberrations between PCFCL and PCLBCL, leg type, which not only suggests that different pathogenetic mechanisms are involved in the development of these two types of CBCL, but also provides additional molecular support for the subdivision used in the WHO-EORTC classification. In addition, this study identified loss of 9p21.3 as a potential prognostic parameter in PCLBCL, leg type.
Patient Selection Pretreatment skin biopsies from 31 patients with the histology of a diffuse large B-cell lymphoma were included in this study. Only cases in which large neoplastic B-cells (CD20 positive) constituted 60% or more of the total number of infiltrating cells were selected. According to the criteria of the recently published WHO-EORTC classification for cutaneous lymphomas, 19 patients were classified as PCFCL and 12 patients as PCLBCL, leg type.1 All PCFCL showed diffuse infiltrates consisting mainly of large centrocytes, which were consistently MUM1 negative, whereas BCL-2 was expressed in only one of 19 cases (case 19). All PCLBCL, leg type, had presented with skin lesions on one or both legs, showed confluent sheets of centroblasts and immunoblasts, which strongly expressed BCL-2 (12 of 12 cases) and MUM1 (seven of seven cases). Since this group contained only patients presenting with skin lesions on one or both legs, this group will further be referred to as PCLBCL, leg type. In all 31 patients there was no evidence of extracutaneous disease at time of diagnosis as assessed by adequate staging procedures including physical examination, CBCs, computed tomography of chest and abdomen and bone marrow biopsy. The relevant clinical and follow-up data of the patients investigated are summarized in Table 1.
Genomic DNA Extraction On average, 10 to 60 µg of genomic DNA was isolated from 25 x 20 µm frozen sections using a commercially available kit as described by the manufacturer (Genomic-tips 20/G kit; Qiagen, Hilden, Germany).
Array-Based CGH
Double-Color Interphase FISH on Nuclei Isolated From Paraffin-Embedded Tissue
Bisulfite Sequence Analysis
We detected both small and whole-chromosome areas of low copy number gain (DNA copy number < 4), high-level DNA amplifications (DNA copy number  4), and deletions (DNA copy number = 0 or 1). In the total group of CBCL, the mean number of chromosomal aberrations was 187 (range, 44 to 649 aberrations per case). Low copy number gains (n = 108) were more frequent than losses (n = 68) and high-level DNA amplifications (n = 11). Recurrent chromosomal alterations, being detected in more than 30% of the total group of 31 patients, included low copy number gains at 12q13-12q14 (62%), 10q24.2 (54%), and 7q21-7q22 (50%), and losses at 6q (41%). Because sex-mismatched DNA was used as reference in the hybridization reaction, Xp and Xq abnormalities could not be identified. Analysis of the two clinical entities, PCFCL (n = 19) and PCLBCL, leg type (n = 12), revealed clear differences in patterns of common chromosomal aberrations (Fig 1A-1C).
The mean number of alterations per patient in the PCFCL group was 184 (range, 52 to 649) with 109 low copy number gains (range, 35 to 353), 10 high-level DNA amplifications (range, 0 to 31), and 66 losses (range, 12 to 265). The most frequent findings in PCFCL (present in > 30% of cases) were low copy number gains at 1q23-1q25 (53%), 7q21-q22 (47%), 12p11.21-22 (37%), and 21q11.2-21q22.3 (37%); high-level DNA amplifications of chromosome 2p16.1 (63%), and deletion of a small region at chromosome 14q32 (68%). In PCLBCL, leg type, the mean number of alterations per patient was 193 (range, 44 to 508) with 108 low copy number gains (range, 19 to 329), 13 high-level DNA amplifications (range, 0 to 37), and 72 losses (range, 20 to 179). The most frequent findings (present in > 30% of cases) were low copy number gains at 14q11.2-14q12 (67%), 12q13-12q14 (83%), 7q21-q22 (58%), and 12p13.2-12p13.33 (50%); a high-level DNA amplification at chromosome 18q21.31-18q21.33; and deletions over a large region in chromosome 6q14.1-6q27 (58%) and 8p23.1 (42%), as well as a small deletion at chromosome 9p21.3 (67%). When investigating the chromosomal aberrations in more detail, we detected several oncogenes and/or tumor suppressor genes to be present in the altered chromosomal regions. Details on chromosomal aberrations for the complete groups, as well as individual cases, are listed in Tables 2 and 3.
Low Copy Number Gain of Chromosome 12q13-12q14 Duplication of 12q13-12q14 was frequently detected both in the group of PCFCL (53%) and in the group of PCLBCL, leg type (83%). Because alteration of this region is often present in B-cell malignancies we investigated the region in more detail. The region of duplication on chromosome 12q was located at 55.0-65.0 Mb and included the CDK4 gene. Using FISH, we confirmed CDK4 gene duplication in patients with gains at 12q13-12q14 (Fig 2).
High-Level DNA Amplification of Chromosome 2p16.1 In PCFCL, we identified amplification corresponding to the BAC clones RP11-440P5 and RP11-373L24, representing a small region on chromosome 2p16.1, as the most common recurrent high-level DNA amplification in 12 (63%) of 19 cases. This amplification was centered at 60.6-61.2 Mb and included the candidate oncogenes BCL11A and c-REL. A representative individual case (case 9) demonstrating this region of amplification is depicted in Figure 2A. Using FISH, we confirmed c-REL gene amplifications in patients with gains at 2p16.1 (Fig 2B; case 3, a typical result for four patients analyzed). In contrast to the PCFCL patients, in the group of PCLBCL, leg type, three (25%) of 12 patients showed alteration of this region. One patient had a whole-chromosome duplication of chromosome 12, and the other two patients showed an amplification of DNA corresponding to BAC clone RP11-440P5 (containing the BCL11A gene) and no amplification of DNA corresponding to BAC clone RP11-373L24 (harboring the c-REL gene). A representative case (case 23) showing amplification of only BCL11A and not c-REL is depicted in Figure 2C.
Deletion of Chromosome 14q32
High-Level DNA Amplification of Chromosome 18q21.31-18q21.33
Deletion of Chromosome 9p21.3 Within the PCLCBL, leg type, group, a common minimally altered region in chromosome arm 9p (clone RP11-149I2) was identified in eight (67%) of 12 patients. All eight patients demonstrated (partial) loss of 9p21.3 (21.9-22.0 Mb) encompassing the CDKN2A (p14/p16INK4A) and CDKN2B (p15INK4B), MTAP, and NSG-x genes. A representative individual case (case 29) demonstrating this specific deletion is shown in Figure 4A. Deletion of the CDKN2A gene was also determined using FISH analysis for those cases showing 9p21.3 loss by array CGH and for which paraffin embedded biopsy material was available (n = 3). FISH confirmed that genomic losses lower than –0.75 (as detected by array-based CGH; cases 29 and 30) were indeed in agreement with homozygous (biallelic) deletion, whereas losses lower than –0.25 correspond to hemizygosity (Fig 4C; case 27). Interestingly, five of five PCLBCL, leg type, patients with a biallelic microdeletion within chromosome 9p21.3 died as a result of the lymphoma, as compared with one of six PCLBCL, leg type, patients without this deletion.
Promoter Hypermethylation Analysis To explore the possibility that patients with unfavorable prognosis, without biallelic loss of 9p21.3, lost expression of CDKN2A and/or CDKN2B due to promoter hypermethylation all cases were analyzed for DNA methylation, using bisulfite sequence analysis. Methylation of CDKN2A was detected in four patients, whereas methylation of the CDKN2B gene could not be demonstrated in any of the 31 cases analyzed. Two patients (cases 25 and 27) showed complete methylation of the CDKN2A promoter region, whereas the other two patients (cases 4 and 24) showed only partial methylation.
A considerable proportion of primary CBCL has the histologic appearance of DLBCL. In the EORTC classification for primary cutaneous lymphomas, most of these lymphomas were classified as primary cutaneous follicle center cell lymphoma, whereas a significant minority was classified as PCLBCL of the leg.13 Differentiation between these two groups is considered to be important, because of differences in prognosis and first choice of treatment, radiotherapy or systemic chemotherapy, respectively. Distinction between these two types of DLBCL mainly on the basis of site of presentation has evoked much debate.21 However, more recent clinical, histologic, immunohistochemical and molecular genetic studies have resulted in a better definition of these two types of CBCL, and confirmed that they are distinct entities.10,22-24 In the recently published WHO-EORTC classification, PCFCL and PCLBCL, leg type, are included as separate entities.1 Notwithstanding, the molecular mechanisms involved in the development of these two types of CBCL are largely unresolved. Moreover, genetic abnormalities allowing differentiation between PCLBCL, leg type, patients with a good or poor prognosis have not yet been identified. In an attempt to resolve some of these issues in the present study, array-based CGH was used to define with high resolution the DNA copy number profiles of 31 patients with the histologic appearance of DLBCL, including 19 patients with PCFCL and 12 patients with PCLBCL, leg type. The results of this study showed clear differences in chromosomal aberrations between both groups of CBCL. The most interesting chromosomal aberrations in the group of PCFCL were high-level amplifications of chromosome 2p16.1 and deletion of chromosome 14q32.33. High-level DNA amplification of a small region of chromosome 2p16.1 containing both the BCL11A and c-REL genes was detected in 12 (63%) of 19 PCFCL cases, but in only three of 12 PCLBCL, leg type, cases. Although in PCFCL, transcription repressor BCL11A is always coamplified with c-REL, two of three PCLBCL, leg type, cases showed amplification of only the BCL11A, but not of the c-REL gene. Amplification of c-REL is frequently found in nodal and extranodal DLBCL, transformed follicular lymphomas and Hodgkin's lymphoma.25-30 In a previous study using classical CGH,14 c-REL amplification was detected in only one of six PCFCL, demonstrating the superior sensitivity of the array-based CGH. These observations further support the concept that PCFCL are similar to germinal center–like DLBCL, because c-REL amplifications are characteristically found in germinal center–like DLBCL.10,31 Loss of chromosome 14q32.33 containing the immunoglobulin heavy chain locus was observed in 13 of 19 PCFCL patients, but in only three of 12 PCLBCL, leg type, patients. Although this region is often involved in translocations, such as t(14;18) in follicular lymphomas and a proportion of DLBCL, t(8;14) in Burkitt lymphoma and t(11;14) in mantle-cell lymphoma, previous studies demonstrated that these translocations do not occur in PCFCL.15 The deletion of chromosome 14q32.33 in PCFCL is in agreement with previous gene expression studies from our group, demonstrating loss of expression of the immunoglobulin heavy chain mRNA as one of the most discriminating factors between both groups, occurring in PCFCL but not in PCLBCL, leg type.10 These results are also in line with previous immunocytochemical studies indicating that PCFCL often lacks expression of surface immunoglobulins.4,6,7 The most interesting observations in the group of PCLBCL, leg type, were high-level DNA amplifications of chromosome 18q21 and deletions of chromosome 9p21.3. High-level DNA amplifications of chromosome 18q21.31-q21.33 encompassing the BCL-2 and MALT1 genes were detected in eight (67%) of 12 PCLBCL, leg type, but in only two (11%) of 19 PCFCLs. Previous studies demonstrated that the MALT1 and BCL-2 gene in PCLBCL are not or are very rarely affected by translocations making this an unlikely cause for the detected DNA amplifications.8,15,32 A more detailed analysis of these PCLBCL, leg type, patients revealed that two patients showed amplification of MALT1 and one patient showed amplification of BCL-2, whereas amplification of both MALT1 and BCL-2 was detected in five patients. BCL-2 gene amplification has been reported previously in nodal DLBCL with 18q21 high-level DNA amplifications as well as in 50% of primary cutaneous DLBCL.25,33-35 However, in this latter study, no distinction was made between PCFCL and PCLBCL, leg type. MALT1 expression may occur in B-cell non-Hodgkin's lymphoma of various histologic subtypes either through translocations involving the immunoglobulin heavy chain locus t(14;18)(q32;q21) or by genomic amplification.36 Translocations involving MALT1 were not detected previously in PCLBCL.15 Our results demonstrate that 18q21 amplification occurs in eight (67%) of 12 of PCLBCL, leg type, and involve the BCL-2 and MALT1 genes. In five of eight patients, both the BCL-2 and MALT1 genes were amplified. Interestingly, we noticed that in one patient, both regions of amplification were separated by normal copy DNA. Together with the detection of selective amplification of DNA regions containing only the MALT1 or the BCL-2 gene in other patients, that instance demonstrates that amplification of these genes can occur as independent events affecting relatively small regions of DNA rather than gross genetic changes involving large chromosomal fragments. Our results are consistent with a recent study that showed that 18q amplifications are more common in activated B-cell–like DLBCL than in germinal center cell–like DLBCL.37 Deletion of a small region on chromosome 9p21.3 containing the CDKN2A and CDKN2B gene loci was detected in eight of 12 PCLBCL, leg type, patients but not in any of the PCFCL patients. Most interestingly, all seven PCLBCL, leg type, patients who died as a result of their lymphoma had a homozygous deletion of 9p21.3 (five cases), promoter hypermethylation of the CDKN2A gene (one case), or hemizygous deletion combined with CDKN2A hypermethylation (one case). Whereas previous studies on large groups of PCLBCL, leg type, patients suggested that a round cell morphology (as opposed to a cleaved cell morphology) and BCL-2 expression are associated with an inferior prognosis,3 in the present study, the neoplastic B-cells in all 12 PCLBCL, leg type patients (seven of whom died as a result of their lymphoma), had a round cell morphology and strongly expressed BCL-2. The observation that loss of CDKN2A (p16INK4A) was associated with inferior survival is therefore of great clinical importance, since it suggests that loss of p16INK4A expression may serve as an important prognostic parameter in this group. Interestingly, loss of CDKN2B (p15INK4B) expression seems to be of less importance; methylation of CDKN2A was observed in all cases with (partial) retention and adverse prognosis, whereas CDKN2B methylation could not be demonstrated. Promoter hypermethylation of CDKN2B and CDKN2A leading to decreased expression of p15 and p16 protein was described in an earlier study on primary cutaneous B-cell lymphomas. Although loss of p16 was described with progression of disease, no relation with prognosis was observed.38 Our results are consistent with a recent study that showed that loss of 9p21.3 is much more common in activated B-cell–like DLBCL than in germinal center–like DLBCL, and that loss of 9p21.3 is associated with an adverse prognosis.37 Deletion at chromosome 9p21 is also a frequent cytogenetic abnormality in other hematologic malignancies, such as acute lymphoblastic leukemia (ALL) or pediatric ALL.39-41 and demonstrated prognostic significance for these genetic changes.42-44 In a recent study, Raschke et al45 proposed that the mechanisms inducing relatively small deletions in the region containing CDKN2A and CDKN2B (as seen in our PCLBCL, leg type, patients) might be the result of exuberant processing during nonhomologous end-joining (NHEJ) DNA repair of double-strand breaks in the locus. Distinct mechanisms typically causing larger deletions, of several megabases, may be prevalent in other tumors such as bladder cancer and glioma.45 Another chromosomal abnormality commonly associated with poor survival is loss of chromosome 6q. However, in the present study, loss of 6q was found in not only seven of 12 PCLBCL, leg type, cases, but also in six of 19 PCFCL cases. Since these latter six patients had an excellent prognosis, it precludes usage of 6q loss as a useful prognostic marker. In conclusion, the results of the present array-based CGH study clearly demonstrate distinct chromosomal aberrations in PCFCL and PCLBCL, leg type, which provides further support for their categorization in the WHO-EORTC classification as separate entities. The most important findings were high-level DNA amplification of 2p16.1 (c-REL/BCL11A) and loss of 14q32.33 in the group of PCFCL, and high-level DNA amplification of chromosome 18q21 and loss of 9p21.3 in the PCLBCL, leg type, group. Finally, although confirmation on a larger group of patients is required, our results suggest that loss of chromosome 9p21.3 might prove to be an important prognostic marker in PCLBCL, leg type.
The authors indicated no potential conflicts of interest.
The authors wish to thank Marja van der Burg (Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands) for her outstanding technical assistance.
Supported by Grant No. 907-00-066 from The Netherlands Organisation for Health Research and Development (M.V.) and a grant from Stichting De Drie Lichten (J.H.). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 2. Berti E, Alessi E, Caputo R, et al: Reticulohistiocytoma of the dorsum. J Am Acad Dermatol 19:259-272, 1988[Medline] 3. Grange F, Bekkenk MW, Wechsler J, et al: Prognostic factors in primary cutaneous large B-cell lymphomas: A European multicenter study. J Clin Oncol 19:3602-3610, 2001 4. Santucci M, Pimpinelli N, Arganini L: Primary cutaneous B-cell lymphoma: A unique type of low-grade lymphoma—Clinicopathologic and immunologic study of 83 cases. Cancer 67:2311-2326, 1991[CrossRef][Medline] 5. Cerroni L, Arzberger E, Putz B, et al: Primary cutaneous follicle center cell lymphoma with follicular growth pattern. Blood 95:3922-3928, 2000 6. Garcia CF, Weiss LM, Warnke RA: Small noncleaved cell lymphoma: An immunophenotypic study of 18 cases and comparison with large cell lymphoma. Hum Pathol 17:454-461, 1986[CrossRef][Medline] 7. Willemze R, Meijer CJ, Scheffer E, et al: Diffuse large cell lymphomas of follicular center cell origin presenting in the skin: A clinicopathologic and immunologic study of 16 patients. Am J Pathol 126:325-333, 1987[Abstract] 8. Geelen FA, Vermeer MH, Meijer CJ, et al: Bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol 16:2080-2085, 1998[Abstract] 9. Hoefnagel JJ, Vermeer MH, Jansen PM, et al: Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: Further support for a follicle centre cell origin and differential diagnostic significance. Br J Dermatol 149:1183-1191, 2003[CrossRef][Medline] 10. Hoefnagel JJ, Dijkman R, Basso K, et al: Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 105:3671-3678, 2004[Medline] 11. de Leval L, Harris NL, Longtine J, et al: Cutaneous b-cell lymphomas of follicular and marginal zone types: Use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and classification. Am J Surg Pathol 25:732-741, 2001[CrossRef][Medline] 12. Vermeer MH, Geelen FA, van Haselen CW, et al: Primary cutaneous large B-cell lymphomas of the legs: A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis—Dutch Cutaneous Lymphoma Working Group. Arch Dermatol 132:1304-1308, 1996 13. Willemze R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: A proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354-371, 1997 14. Hallermann C, Kaune KM, Siebert R, et al: Chromosomal aberration patterns differ in subtypes of primary cutaneous B cell lymphomas. J Invest Dermatol 122:1495-1502, 2004[CrossRef][Medline] 15. Hallermann C, Kaune KM, Gesk S, et al: Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol 123:213-219, 2004[CrossRef][Medline] 16. Knijnenburg J, Szuhai K, Giltay J, et al: Insights from genomic microarrays into structural chromosome rearrangements. Am J Med Genet A 132:36-40, 2005[Medline] 17. Raap AK, van der Burg MJ, Knijnenburg J, et al: Array comparative genomic hybridization with cyanin cis-platinum-labeled DNAs. Biotechniques 37:130-134, 2004[Medline] 18. Haralambieva E, Kleiverda K, Mason DY, et al: Detection of three common translocation breakpoints in non-Hodgkin's lymphomas by fluorescence in situ hybridization on routine paraffin-embedded tissue sections. J Pathol 198:163-170, 2002[CrossRef][Medline] 19. Jordanova ES, Riemersma SA, Philippo K, et al: Hemizygous deletions in the HLA region account for loss of heterozygosity in the majority of diffuse large B-cell lymphomas of the testis and the central nervous system. Genes Chromosomes Cancer 35:38-48, 2002[CrossRef][Medline] 20. van Doorn R, Zoutman WH, Dijkman R, et al: Epigenetic profiling of cutaneous T-cell lymphoma: Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 23:3886-3896, 2005 21. Jaffe ES, Sander CA, Flaig MJ: Cutaneous lymphomas: A proposal for a unified approach to classification using the R.E.A.L./WHO Classification. Ann Oncol 11:17-21, 2000 (suppl 1) 22. Goodlad JR, Krajewski AS, Batstone PJ, et al: Primary cutaneous diffuse large B-cell lymphoma: Prognostic significance of clinicopathological subtypes. Am J Surg Pathol 27:1538-1545, 2003[CrossRef][Medline] 23. Paulli M, Viglio A, Vivenza D, et al: Primary cutaneous large B-cell lymphoma of the leg: Histogenetic analysis of a controversial clinicopathologic entity. Hum Pathol 33:937-943, 2002[CrossRef][Medline] 24. Yap LM, Blum R, Foley P, et al: Clinical study of primary cutaneous B-cell lymphoma using both the European Organization for Research and Treatment of Cancer and World Health Organization classifications. Australas J Dermatol 44:110-115, 2003[CrossRef][Medline] 25. Rao PH, Houldsworth J, Dyomina K, et al: Chromosomal and gene amplification in diffuse large B-cell lymphoma. Blood 92:234-240, 1998 26. Martinez-Climent JA, Alizadeh AA, Segraves R, 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 101:3109-3117, 2003 27. Joos S, Otano-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 87:1571-1578, 1996 28. Joos S, Menz CK, Wrobel G, et al: Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 99:1381-1387, 2002 29. Barth TF, Dohner H, Werner CA, et al: Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastrointestinal tract. Blood 91:4321-4330, 1998 30. Barth TF, Martin-Subero JI, Joos S, et al: Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood 101:3681-3686, 2003 31. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937-1947, 2002 32. Child FJ, Russell-Jones R, Woolford AJ, et al: Absence of the t(14;18) chromosomal translocation in primary cutaneous B-cell lymphoma. Br J Dermatol 144:735-744, 2001[CrossRef][Medline] 33. Mao X, Lillington D, Child F, et al: Comparative genomic hybridization analysis of primary cutaneous B-cell lymphomas: Identification of common genomic alterations in disease pathogenesis. Genes Chromosomes Cancer 35:144-155, 2002[CrossRef][Medline] 34. Monni O, Joensuu H, Franssila K, et al: DNA copy number changes in diffuse large B-cell lymphoma: Comparative genomic hybridization study. Blood 87:5269-5278, 1996 35. Wessendorf S, Schwaenen C, Kohlhammer H, et al: Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization. Oncogene 22:1425-1429, 2003[CrossRef][Medline] 36. Sanchez-Izquierdo D, Buchonnet G, Siebert R, et al: MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 101:4539-4546, 2003 37. Tagawa H, Suguro M, Tsuzuki S, et al: Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma. Blood 106:1770-1777, 2005 38. Child FJ, Scarisbrick JJ, Calonje E, et al: Inactivation of tumor suppressor genes p15(INK4b) and p16(INK4a) in primary cutaneous B cell lymphoma. J Invest Dermatol 118:941-948, 2002[CrossRef][Medline] 39. Okuda T, Shurtleff SA, Valentine MB, et al: Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood 85:2321-2330, 1995 40. Olopade OI, Bohlander SK, Pomykala H, et al: Mapping of the shortest region of overlap of deletions of the short arm of chromosome 9 associated with human neoplasia. Genomics 14:437-443, 1992[CrossRef][Medline] 41. Pollak C, Hagemeijer A: Abnormalities of the short arm of chromosome 9 with partial loss of material in hematological disorders. Leukemia 1:541-548, 1987[Medline] 42. Heyman M, Rasool O, Borgonovo BL, et al: Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia. J Clin Oncol 14:1512-1520, 1996 43. Kees UR, Burton PR, Lu C, et al: Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. Blood 89:4161-4166, 1997 44. Zhou M, Gu L, Yeager AM, et al: Incidence and clinical significance of CDKN2/MTS1/P16ink4A and MTS2/P15ink4B gene deletions in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 14:141-150, 1997[Medline] 45. Raschke S, Balz V, Efferth T, et al: Homozygous deletions of CDKN2A caused by alternative mechanisms in various human cancer cell lines. Genes Chromosomes Cancer 42:58-67, 2005[CrossRef][Medline] Submitted March 25, 2005; accepted August 8, 2005.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
50%).
