Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas

Houldsworth, Jane; Olshen, Adam B.; Cattoretti, Giorgio; Donnelly, Gerard; Teruya‐Feldstein, Julie; Qin, Jing; Palanisamy, Nallasivam; Shen, Yingjing; Dyomina, Katerina; Petlakh, Marina; Pan, Qiulu; Zelenetz, Andrew D.; Dalla‐Favera, Riccardo; Chaganti, R. S. K.

doi:10.1182/blood-2003-04-1359

Cited by 89 publications

(90 citation statements)

References 35 publications

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“…Gain of chromosome 2p has been identified as a recurrent alteration in 20% of DLBCL, (9)(10)(11)(12)(13)(14)(15) 50% of cHL, (16,17) and 3-47% of PMBCL cases. (11,14,15) In previous studies, CGH and FISH analyses were used as tools to investigate genomic alterations.…”

Section: Discussionmentioning

confidence: 99%

“…(7) Amplification at the 2p arm has been reported in B-cell lymphomas, such as DLBCL, (9)(10)(11)(12)(13)(14)(15) classical Hodgkin's lymphoma (cHL), (16,17) follicular lymphoma (FL) (18) and primary mediastinal B-cell lymphoma (PMBCL). (11,14,15) The two candidate genes, REL and BCL11A, have been mapped within this 2p15 -16 amplicon.…”

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confidence: 99%

“…(6,7) It has been useful not only for genome scanning of tumor cells but also for identification of novel oncogenes and suppressor genes. (8) We previously used a genome-wide array-CGH to identify a gain of 2p15 -16 in 25 out of 99 DLBCL cases.(7) Amplification at the 2p arm has been reported in B-cell lymphomas, such as DLBCL, (9)(10)(11)(12)(13)(14)(15) classical Hodgkin's lymphoma (cHL), (16,17) follicular lymphoma (FL) (18) and primary mediastinal B-cell lymphoma (PMBCL). (11,14,15) The two candidate genes, REL and BCL11A, have been mapped within this 2p15 -16 amplicon.…”

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Characterization of target genes at the 2p15–16 amplicon in diffuse large B‐cell lymphoma

et al. 2006

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Amplification of 2p has been observed as a recurrent alteration in diffuse large B-cell lymphoma (DLBCL). Whereas two candidate oncogenes, REL and BCL11A, have been investigated as targets for 2p amplification, the question remains as to whether the true target gene in the amplicon is REL, BCL11A or both. We previously identified frequent genomic gains of chromosomal 2p in 25 out of 99 DLBCL cases by means of genome-wide array comparative genomic hybridization (CGH). All of these 25 cases included recurrent copy number gain at 2p15-16. In the study presented here, cases were analyzed in greater detail by means of contig bacterial artificial chromosome (BAC) array CGH for the 4.5-Mb region at 2p15-16, which contained 33 BAC clones. We confined the minimal common region to 500-kb in length, where only the candidate oncogene REL, and not BCL11A, is located. Real-time quantitative PCR was carried out to investigate the correlation between genomic gain and expression. It showed a significant correlation for both genes, indicating that these two genes are common targets for the 2p15-16 amplicon. However, given the fact that REL is more frequently amplified than BCL11A, the REL gene may play a more important role than BCL11A in the pathogenesis of DLBCL. (Cancer Sci 2006; 97: 499-504) D iffuse large B cell lymphoma (DLBCL) is the most common type of malignant lymphoma, accounting for 30% of adult non-Hodgkin's lymphoma.(1) However, clinicopathological and genetic heterogeneities in this entity have suggested that further refinement of its subgroups is required.(2-5) Array-based comparative genomic hybridization (array-CGH) analysis is a powerful tool to identify genomic imbalances characteristic of distinct subgroups in DLBCL. (6,7) It has been useful not only for genome scanning of tumor cells but also for identification of novel oncogenes and suppressor genes. (8) We previously used a genome-wide array-CGH to identify a gain of 2p15 -16 in 25 out of 99 DLBCL cases.(7) Amplification at the 2p arm has been reported in B-cell lymphomas, such as DLBCL, (9)(10)(11)(12)(13)(14)(15) classical Hodgkin's lymphoma (cHL), (16,17) follicular lymphoma (FL) (18) and primary mediastinal B-cell lymphoma (PMBCL). (11,14,15) The two candidate genes, REL and BCL11A, have been mapped within this 2p15 -16 amplicon. The REL proto-oncogene, which encodes a member of the NF-κB transcription factor family, has frequently been found amplified in B-cell lymphomas. BCL11A, which is located quite near REL on chromosome 2p15 -16, is coamplified with REL in DLBCL and cHL. (12,15,16) In spite of numerous studies of this region, the question remains whether the target gene in the 2p15-16 amplification is REL, BCL11A, or both.For the study presented here, we carried out a contig array-CGH using glass slides on which contiguously ordered bacterial artificial chromosome (BAC) clones were spotted throughout 4.5 Mb of the 2p15 -16 genome to confine the minimal common region of amplification at 2p15 -16 in DLBCL cases. Real-time quantitative-polymerase ch...

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confidence: 99%

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Characterization of target genes at the 2p15–16 amplicon in diffuse large B‐cell lymphoma

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“…With regard to these findings, gains in 2p16 were most frequent in patients who failed to achieve a CR. It is noteworthy that a gain in chromosome 2p has been identified as a recurrent alteration in 20% of patients DLBCL 12,[31][32][33][34][35][36][37] and is the most frequent CGH alteration in classic Hodgkin lymphoma (identified in 50% of patients). 38,39 The common recurrent region expands 4.2 Mb in 2p15-16.…”

Section: Discussionmentioning

confidence: 99%

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Robledo¹,

Garcı́a²,

Caballero³

et al. 2009

Cancer

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BACKGROUND: Diffuse large B‐cell lymphomas (DLBCLs) are the most common type of non‐Hodgkin lymphomas. With chemotherapy and progenitor stem cell transplantation, about 60% of patients with DLBCL are long‐term survivors. The International Prognostic Index identifies patients with different outcomes. However, biologic characteristics also may help to discriminate different treatments groups. METHODS: DNA copy number changes identified by array comparative genomic hybridization (array‐CGH) were studied in 40 patients who had DLBCL with a poor prognosis and who were treated uniformly with dose‐escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and intensification before high‐dose chemotherapy with autologous stem cell transplantation. RESULTS: In total, 722 copy number changes were observed (median, 5 copy number changes per patient; range, 0‐75 copy number changes per patient), with a predominance of gains. Gains on 2p16 were present only in patients who failed to achieve a complete response after escalated CHOP therapy (P < .05). In univariate analysis, gains on 2p16 and losses on 17p13 (the tumor protein p53 gene TP53 gene) were associated with a poor response to the therapy. Furthermore, age >60 years and losses on 10q23.31 (the phosphatase and tensin homolog gene PTEN) or on 17p13 were associated with short survival. In multivariate analysis, only advanced age and losses on 10q23.31 retained an adverse prognostic impact. CONCLUSIONS: Array‐CGH identified multiple regions with common copy number changes, some of which were associated with outcome in patients with DLBCL. Cancer 2009. © 2009 American Cancer Society.

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“…Gene expression profiling results were analyzed first by principalcomponent analysis (PCA) using a list of 146 probe sets that represented 62 genes that are characteristic of ABC or GC signature. 33 This analysis identified 5 LBCL samples with an ABC cell signature and distinguished them from the 5 samples of LBCL with a GC signature (Fig. 1A).…”

Section: Gene Expression Analysismentioning

confidence: 99%

The feasibility of gene expression profiling generated in fine-needle aspiration specimens from patients with follicular lymphoma and diffuse large B-cell lymphoma

Goy

Stewart

Barkoh

et al. 2005

Cancer

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Lymphoma of germinal center cell (GC) origin generally is an indolent malignancy that transforms progressively into a more aggressive disease. According to the World Health Organization classification, lymphomas of follicular center cell origin are classified as either large B-cell lymphoma (LBCL) or follicular lymphoma (FL).The authors tested the feasibility of performing gene expression profiling using amplified RNA from fine-needle aspirates (FNA) obtained from lymph nodes.Twenty-four samples from patients with a diagnosis of FL or LBCL were obtained after Institutional Review Board-approved informed consent was obtained. The diagnoses were confirmed by 2 pathologists and were classified into 2 groups (10 LBCL samples and 14 FL samples) by using conventional morphology and immunophenotyping. One hundred nanograms of total RNA were subjected to 2 cycles of standard, double-stranded complementary DNA synthesis and in vitro transcription for target amplification using a small-sample target-labeling protocol.

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Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas

Abstract: Although it has been suggested that REL is the critical target gene of 2p12-16 amplification in diffuse large B-cell lymphoma (DLBCL), little experimental evidence supports this notion. In the present study, we sought to evaluate the relationship between REL amplification and REL func-

Cited by 89 publications

References 35 publications

Characterization of target genes at the 2p15–16 amplicon in diffuse large B‐cell lymphoma

Characterization of target genes at the 2p15–16 amplicon in diffuse large B‐cell lymphoma

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

The feasibility of gene expression profiling generated in fine-needle aspiration specimens from patients with follicular lymphoma and diffuse large B-cell lymphoma

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