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García R, Hussain A, Chen W, Wilson K, Koduru P. An artificial intelligence system applied to recurrent cytogenetic aberrations and genetic progression scores predicts MYC rearrangements in large B-cell lymphoma. EJHAEM 2022; 3:707-721. [PMID: 36051032 PMCID: PMC9421965 DOI: 10.1002/jha2.451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/05/2022] [Accepted: 04/09/2022] [Indexed: 11/20/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is characterized by MYC rearrangements (MYC R) in up to 15% of cases, and these have unfavorable prognosis. Due to cryptic rearrangements and variations in MYC breakpoints, MYC R may be undetectable by conventional methods in up to 10%-15% of cases. In this study, a retrospective proof of concept study, we sought to identify recurrent cytogenetic aberrations (RCAs), generate genetic progression scores (GP) from RCAs and apply these to an artificial intelligence (AI) algorithm to predict MYC status in the karyotypes of published cases. The developed AI algorithm is validated for its performance on our institutional cases. In addition, cytogenetic evolution pattern and clinical impact of RCAs was performed. Chromosome losses were associated with MYC-, while partial gain of chromosome 1 was significant in MYC R tumors. MYC R was the sole driver alteration in MYC-rearranged tumors, and evolution patterns revealed RCAs associated with gene expression signatures. A higher GPS value was associated with MYC R tumors. A subsequent AI algorithm (composed of RCAs + GPS) obtained a sensitivity of 91.4 and specificity of 93.8 at predicting MYC R. Analysis of an additional 59 institutional cases with the AI algorithm showed a sensitivity and specificity of 100% and 87% each with positive predictive value of 92%, and a negative predictive value of 100%. Cases with a MYC R showed a shorter survival.
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Affiliation(s)
- Rolando García
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
| | - Anas Hussain
- Deccan College of Medical SciencesHyderabadIndia
| | - Weina Chen
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
| | - Kathleen Wilson
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
| | - Prasad Koduru
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
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2
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Cryptic MYC insertions in Burkitt lymphoma: New data and a review of the literature. PLoS One 2022; 17:e0263980. [PMID: 35167621 PMCID: PMC8846522 DOI: 10.1371/journal.pone.0263980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 02/01/2022] [Indexed: 12/24/2022] Open
Abstract
The occurrence of MYC-negative Burkitt lymphoma (BL) has been discussed for many years. The real frequency of the MYC insertion in MYC-negative BL is still unknown. Fine-needle aspiration biopsies of 108 consecutive patients with clinicopathologically suspected BL (suspBL) were evaluated by flow cytometry, classical cytogenetics, and fluorescence in situ hybridization (FISH). We found 12 cases (11%) without the MYC rearrangement by FISH with a MYC breakapart probe: two patients (1.9%) with cryptic MYC/IGH fusion (finally diagnosed as BL) and 10 patients (9.3%) with 11q gain/loss (finally diagnosed as Burkitt-like lymphoma with 11q aberration). The exact breakpoints of the cryptic MYC/IGH were investigated by next-generation sequencing. The MYC insertions’ breakpoints were identified in PVT1 in the first case, and 42 kb upstream of 5′MYC in the second case. To date, a molecular characterization of the MYC insertion in BL has only been reported in one case. Detailed descriptions of our MYC insertions in a routinely and consecutively diagnosed suspBL cohort will contribute to resolving the issue of MYC negativity in BL. In our opinion, the presence of the MYC insertions in BL and other lymphomas might be underestimated, because routine genetic diagnostics are usually based on FISH only, without karyotyping.
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Horn H, Kalmbach S, Wagener R, Staiger AM, Hüttl K, Mottok A, Bens S, Traverse-Glehen A, Fontaine J, Siebert R, Rosenwald A, Ott G. A Diagnostic Approach to the Identification of Burkitt-like Lymphoma With 11q Aberration in Aggressive B-Cell Lymphomas. Am J Surg Pathol 2021; 45:356-364. [PMID: 33136583 DOI: 10.1097/pas.0000000000001613] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Rare cases of aggressive B-cell lymphomas with a morphology similar to Burkitt lymphoma (BL) present with the BL-typical immunophenotype, but lacked MYC translocation (MYC-negative Burkitt-like lymphoma: mnBLL). A proportion of those with an imbalance pattern in chromosome 11q has been designated Burkitt-like lymphoma with 11q aberration in the recent update of the World Health Organization (WHO) classification. Because of the problems in the identification of Burkitt-like lymphoma with 11q aberration, our goal was to retrospectively analyze their frequency in a cohort of "candidate" aggressive lymphomas (cohort 1, n=35) such as mnBLL (n=16), diffuse large B-cell lymphoma with similarities to Burkitt lymphoma (DLBCL-BL; n=3), high-grade B-cell lymphomas, not otherwise specified (NOS) (n=16), as well as in a cohort of MYC-negative diffuse large B-cell lymphoma NOS (cohort 2, n=62). In total, 17/33 cohort 1 cases (52%) harbored the typical 11q aberration pattern, predominantly those that had been classified as mnBLL (12/16, 75%), but also as DLBCL-BL (2/3, 67%) and high-grade B-cell lymphomas, NOS (3/14; 21%). The specimens with this typical 11q aberration pattern were usually negative for the BCL2 protein. Of interest and as a new finding, samples harboring the 11q aberration pattern were often characterized by strikingly coarse apoptotic debris within starry sky macrophages facilitating their recognition. In contrast, only 1 of 62 garden variety DLBCL, NOS was positive for the 11q aberration pattern. In 2 DLBCL-BL, a dual MYC translocation/11q aberration pattern was detected. As a diagnostic algorithm, we, therefore, propose analysis of 11q status in MYC-negative high-grade lymphomas with features of BL, especially showing BCL2 negativity and a conspicuous coarse apoptotic debris in starry sky macrophages.
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Affiliation(s)
- Heike Horn
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart
- University of Tübingen, Tübingen
| | - Sabrina Kalmbach
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
- University of Tübingen, Tübingen
| | - Rabea Wagener
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf
| | - Annette M Staiger
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart
- University of Tübingen, Tübingen
| | - Katrin Hüttl
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart
| | - Anja Mottok
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Susanne Bens
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Alexandra Traverse-Glehen
- Service d'Anatomie Pathologie, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Juliette Fontaine
- Service d'Anatomie Pathologie, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Reiner Siebert
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Andreas Rosenwald
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart
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4
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Mundo L, Ambrosio MR, Raimondi F, Del Porro L, Guazzo R, Mancini V, Granai M, Jim Rocca B, Lopez C, Bens S, Onyango N, Nyagol J, Abinya N, Navari M, Ndede I, Patel K, Paolo Piccaluga P, Bob R, de Santi MM, Russell RB, Lazzi S, Siebert R, Stein H, Leoncini L. Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases. Blood Cancer J 2019; 9:91. [PMID: 31748534 PMCID: PMC6868231 DOI: 10.1038/s41408-019-0252-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 07/29/2019] [Accepted: 08/19/2019] [Indexed: 12/21/2022] Open
Abstract
MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
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Affiliation(s)
- Lucia Mundo
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | | | | | | | - Raffaella Guazzo
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Virginia Mancini
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Massimo Granai
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Bruno Jim Rocca
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Cristina Lopez
- Ulm University and Ulm University Medical Center, Ulm, Germany
| | - Susanne Bens
- Ulm University and Ulm University Medical Center, Ulm, Germany
| | | | | | | | - Mohsen Navari
- Department of Medical Biotechnology & Research Center of Advanced Technologies in Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | | | | | - Pier Paolo Piccaluga
- Department of Experimental, Diagnostic, and Specialty Medicine Bologna University Medical School, S. Orsola Malpighi Hospital, Bologna and Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
- Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya
| | | | | | - Robert B Russell
- Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany
| | - Stefano Lazzi
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Reiner Siebert
- Ulm University and Ulm University Medical Center, Ulm, Germany
| | | | - Lorenzo Leoncini
- Department of Medical Biotechnology, University of Siena, Siena, Italy.
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Liu Y, Bian T, Zhang Y, Zheng Y, Zhang J, Zhou X, Xie J. A combination of LMO2 negative and CD38 positive is useful for the diagnosis of Burkitt lymphoma. Diagn Pathol 2019; 14:100. [PMID: 31484540 PMCID: PMC6727582 DOI: 10.1186/s13000-019-0876-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 08/23/2019] [Indexed: 12/05/2022] Open
Abstract
Background To evaluate the clinical utility of LIM Domain Only 2 (LMO2) negative and CD38 positive in diagnosis of Burkitt lymphoma (BL). Methods LMO2 and CD38 expression determined by immunohistochemistry in 75 BL, 12 High-grade B-cell lymphoma, NOS (HGBL,NOS) and 3 Burkitt-like lymphomas with the 11q aberration. Results The sensitivity and specificity of LMO2 negative for detecting BL were 98.67 and 100%, respectively; those of CD38 positive were 98.67 and 66.67%, respectively. The sensitivity and specificity of a combination of both for detecting BL were 97.33 and 100%, respectively. In our study, the combined LMO2 negative and CD38 positive results had a higher area under the curve than either LMO2 negative or CD38 positive alone. Conclusions A combination of LMO2 negative and CD38 positive is useful for the diagnosis of Burkitt lymphoma.
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Affiliation(s)
- Yifei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Tingting Bian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Yanlin Zhang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China
| | - Yuanyuan Zheng
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China
| | - Jianguo Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Xiaoge Zhou
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China.
| | - Jianlan Xie
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China.
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6
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Wagener R, Bens S, Toprak UH, Seufert J, López C, Scholz I, Herbrueggen H, Oschlies I, Stilgenbauer S, Schlesner M, Klapper W, Burkhardt B, Siebert R. Cryptic insertion of MYC exons 2 and 3 into the immunoglobulin heavy chain locus detected by whole genome sequencing in a case of " MYC-negative" Burkitt lymphoma. Haematologica 2019; 105:e202-e205. [PMID: 31073073 DOI: 10.3324/haematol.2018.208140] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Rabea Wagener
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Susanne Bens
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Umut H Toprak
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg.,German Caner Research Center (DKFZ), Division of Neuroblastoma Genomics Heidelberg.,Faculty of Biosciences, Heidelberg University, Heidelberg
| | - Julian Seufert
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg.,Faculty of Biosciences, Heidelberg University, Heidelberg
| | - Cristina López
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Ingrid Scholz
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg
| | - Heidi Herbrueggen
- Department of Pediatric Hematology and Oncology, NHL-BFM Study Center, University Children's Hospital, Münster
| | - Ilske Oschlies
- Hematopathology Section, Christian-Albrechts University, Kiel
| | | | - Matthias Schlesner
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg
| | - Wolfram Klapper
- Hematopathology Section, Christian-Albrechts University, Kiel
| | - Birgit Burkhardt
- Department of Pediatric Hematology and Oncology, NHL-BFM Study Center, University Children's Hospital, Münster
| | - Reiner Siebert
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
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7
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Scott DW, Rimsza LM. Dissecting aggressive B-cell lymphoma through genomic analysis - What is clinically relevant? Best Pract Res Clin Haematol 2018; 31:187-198. [PMID: 30213388 DOI: 10.1016/j.beha.2018.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 06/21/2018] [Accepted: 07/02/2018] [Indexed: 10/28/2022]
Abstract
The aggressive B-cell lymphomas are a diverse collection of cancers grouped together based on clinical behavior and derivation from B lymphocytes. Genomic analyses on these tumours are now translating into improved classification systems and identification of underpinning targetable biology. Simple karyotyping revealed key translocations involving MYC, BCL2, and BCL6 that have impacted lymphoma classification in the World Health Organization classification scheme. Subsequently, gene expression profiling identified molecular subgroups within the most common lymphoma, diffuse large B-cell lymphoma (DLBCL): activated B-cell-like and germinal centre B-cell-like. Finally, next generation sequencing has revealed a modest number of frequently mutated genes and a long list of infrequent mutations. The mutational landscapes involve diverse genes associated with dysregulated signalling, epigenetic modification, blockade of cellular differentiation, and immune evasion. These mutational "signatures" are enriched in the different aggressive lymphoma subtypes impacting phenotypes and identifying therapeutic targets. Challenges to implementing genomic assays into clinical practice remain.
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Affiliation(s)
- David W Scott
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Lisa M Rimsza
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
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8
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Mazzoccoli L, Robaina MC, Apa AG, Bonamino M, Pinto LW, Queiroga E, Bacchi CE, Klumb CE. MiR-29 silencing modulates the expression of target genes related to proliferation, apoptosis and methylation in Burkitt lymphoma cells. J Cancer Res Clin Oncol 2018; 144:483-497. [PMID: 29318382 DOI: 10.1007/s00432-017-2575-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/28/2017] [Indexed: 12/22/2022]
Abstract
PURPOSE Burkitt lymphoma (BL) is a B-cell lymphoma frequently diagnosed in children. It is characterized by MYC translocations, which lead to the constitutive expression of the MYC oncogene. MYC contributes to miR-29 repression through an E-box MYC binding site on the miR-29b-1/miR-29a promoter region. We evaluated the role of miR-29a/b/c and their predicted targets in BL pathogenesis. METHODS Mature sequences of miR-29a/b/c were transfected to the BL cell lines BL41 and Raji, and evaluated for DNMT3B, MCL1, BIM, CDK6, AKT and TCL1 protein expression as well as for MCL-1 and CDK6 mRNA expression. BL cells were treated with 5-aza-2'-deoxycytidine (decitabine) and evaluated for miR29 expressions and methylation status. DNMT3B inhibition was performed by DNMT3B siRNA. RESULTS Ectopic expression of miR-29s in BL cells decreased CDK6, DNMT3B, TCL1 and MCL-1 protein levels, but CDK6 and MCL-1 mRNA expression was unaffected by miR-29. Decitabine enhanced miR-29 expression levels and decreased CDK6 protein expression. Additionally, inhibition of DNMT3B by siRNA increased miR-29a/b expression. Notably, the miR-29a/b1 and miR-29b2/c promoter genes showed methylated CpG sequences that were demethylated after decitabine treatments. Furthermore, MYC-negative tumours had higher levels of miR-29 expression compared with MYC-translocated cases, suggesting that MYC regulates miR-29 in BL tumours. CONCLUSIONS Our results suggest a significant role for miR-29s in BL pathogenesis in altering the expression of targets involved in critical cancer pathways, such as cell cycle control, apoptosis inhibition and DNA methylation. Moreover, methylation-mediated miR-29 epigenetic silencing may occur during BL development.
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Affiliation(s)
- Luciano Mazzoccoli
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Marcela Cristina Robaina
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | | | - Martin Bonamino
- Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
- Fundação Instituto Oswaldo Cruz, Vice-presidência de Pesquisa e Laboratórios de Referência, Rio de Janeiro, Brazil
| | | | - Eduardo Queiroga
- Laboratório Bacchi, Consultoria em Patologia, Botucatu, São Paulo, Brazil
| | - Carlos E Bacchi
- Laboratório Bacchi, Consultoria em Patologia, Botucatu, São Paulo, Brazil
| | - Claudete Esteves Klumb
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
- Laboratório de Hemato-Oncologia Celular e Molecular, Instituto Nacional de Câncer, Praça da Cruz Vermelha, 23, 6° andar, ala C, Rio de Janeiro, RJ, CEP: 20230-130, Brazil.
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9
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Rimsza L, Pittaluga S, Dirnhofer S, Copie-Bergman C, de Leval L, Facchetti F, Pileri S, Rosenwald A, Wotherspoon A, Fend F. The clinicopathologic spectrum of mature aggressive B cell lymphomas. Virchows Arch 2017; 471:453-466. [DOI: 10.1007/s00428-017-2199-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 07/04/2017] [Accepted: 07/07/2017] [Indexed: 12/23/2022]
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10
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Lai C, Roschewski M, Melani C, Pittaluga S, Shovlin M, Steinberg SM, Dunleavy K, Pack S, Jaffe ES, Wilson WH. MYC gene rearrangement in diffuse large B-cell lymphoma does not confer a worse prognosis following dose-adjusted EPOCH-R. Leuk Lymphoma 2017. [PMID: 28641474 DOI: 10.1080/10428194.2017.1339882] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Catherine Lai
- a Myeloid Malignancies Section, Hematology Branch, National Heart, Lung, and Blood Institute , National Institutes of Health , Bethesda , MD , USA
| | - Mark Roschewski
- b Lymphoid Malignancies Branch , Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Christopher Melani
- b Lymphoid Malignancies Branch , Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Stefania Pittaluga
- c Laboratory of Pathology , Clinical Center, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Margaret Shovlin
- b Lymphoid Malignancies Branch , Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Seth M Steinberg
- d Biostatistics and Data Management Section , Office of the Clinical Director, Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Kieron Dunleavy
- b Lymphoid Malignancies Branch , Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Svetlana Pack
- c Laboratory of Pathology , Clinical Center, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Elaine S Jaffe
- c Laboratory of Pathology , Clinical Center, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Wyndham H Wilson
- b Lymphoid Malignancies Branch , Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
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Jiang M, Bennani NN, Feldman AL. Lymphoma classification update: B-cell non-Hodgkin lymphomas. Expert Rev Hematol 2017; 10:405-415. [DOI: 10.1080/17474086.2017.1318053] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Manli Jiang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Andrew L. Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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12
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Nguyen L, Papenhausen P, Shao H. The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects. Genes (Basel) 2017; 8:genes8040116. [PMID: 28379189 PMCID: PMC5406863 DOI: 10.3390/genes8040116] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/27/2017] [Accepted: 03/27/2017] [Indexed: 12/25/2022] Open
Abstract
c-MYC is one of the most essential transcriptional factors, regulating a diverse array of cellular functions, including proliferation, growth, and apoptosis. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas, but is rarely reported in T-cell lymphomas. c-MYC dysregulation induces lymphomagenesis by loss of the tight control of c-MYC expression, leading to overexpression of intact c-MYC protein, in contrast to the somatic mutations or fusion proteins seen in many other oncogenes. Dysregulation of c-MYC in B-cell lymphomas occurs either as a primary event in Burkitt lymphoma, or secondarily in aggressive lymphomas such as diffuse large B-cell lymphoma, plasmablastic lymphoma, mantle cell lymphoma, or double-hit lymphoma. Secondary c-MYC changes include gene translocation and gene amplification, occurring against a background of complex karyotype, and most often confer aggressive clinical behavior, as evidenced in the double-hit lymphomas. In low-grade B-cell lymphomas, acquisition of c-MYC rearrangement usually results in transformation into highly aggressive lymphomas, with some exceptions. In this review, we discuss the role that c-MYC plays in the pathogenesis of B-cell lymphomas, the molecular alterations that lead to c-MYC dysregulation, and their effect on prognosis and diagnosis in specific types of B-cell lymphoma.
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Affiliation(s)
- Lynh Nguyen
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
| | - Peter Papenhausen
- Cytogenetics Laboratory, Laboratory Corporation of America, Research Triangle Park, NC 27709, USA.
| | - Haipeng Shao
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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13
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Definition of MYC genetic heteroclonality in diffuse large B-cell lymphoma with 8q24 rearrangement and its impact on protein expression. Mod Pathol 2016; 29:844-53. [PMID: 27125356 DOI: 10.1038/modpathol.2016.71] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/01/2016] [Accepted: 03/06/2016] [Indexed: 12/24/2022]
Abstract
MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression.
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Liew M, Rowe L, Clement PW, Miles RR, Salama ME. Validation of break-apart and fusion MYC probes using a digital fluorescence in situ hybridization capture and imaging system. J Pathol Inform 2016; 7:20. [PMID: 27217970 PMCID: PMC4872483 DOI: 10.4103/2153-3539.181764] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 03/15/2016] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Detection of MYC translocations using fluorescence in situ hybridization (FISH) is important in the evaluation of lymphomas, in particular, Burkitt lymphoma and diffuse large B-cell lymphoma. Our aim was to validate a digital FISH capture and imaging system for the detection of MYC 8q24 translocations using LSI-MYC (a break-apart probe) and MYC 8;14 translocation using IGH-MYC (a fusion probe). MATERIALS AND METHODS LSI-MYC probe was evaluated using tissue sections from 35 patients. IGH-MYC probe was evaluated using tissue sections from forty patients. Sections were processed for FISH and analyzed using traditional methods. FISH slides were then analyzed using the GenASIs capture and analysis system. RESULTS Results for LSI-MYC had a high degree of correlation between traditional method of FISH analysis and digital FISH analysis. Results for IGH-MYC had a 100% concordance between traditional method of FISH analysis and digital FISH analysis. CONCLUSION Annotated whole slide images of H and E and FISH sections can be digitally aligned, so that areas of tumor within a section can be matched and evaluated with a greater degree of accuracy. Images can be archived permanently, providing a means for examining the results retrospectively. Digital FISH imaging of the MYC translocations provides a better diagnostic tool compared to traditional methods for evaluating lymphomas.
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Affiliation(s)
- Michael Liew
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA
| | - Leslie Rowe
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA
| | - Parker W Clement
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| | - Rodney R Miles
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| | - Mohamed E Salama
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
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15
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Cai Q, Medeiros LJ, Xu X, Young KH. MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management. Oncotarget 2015; 6:38591-38616. [PMID: 26416427 PMCID: PMC4770723 DOI: 10.18632/oncotarget.5774] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 09/04/2015] [Indexed: 01/09/2023] Open
Abstract
MYC, a potent oncogene located at chromosome locus 8q24.21, was identified initially by its involvement in Burkitt lymphoma with t(8;14)(q24;q32). MYC encodes a helix-loop-helix transcription factor that accentuates many cellular functions including proliferation, growth and apoptosis. MYC alterations also have been identified in other mature B-cell neoplasms and are associated with aggressive clinical behavior. There are several regulatory factors and dysregulated signaling that lead to MYC up-regulation in B-cell lymphomas. One typical example is the failure of physiological repressors such as Bcl6 or BLIMP1 to suppress MYC over-expression. In addition, MYC alterations are often developed concurrently with other genetic alterations that counteract the proapoptotic function of MYC. In this review, we discuss the physiologic function of MYC and the role that MYC likely plays in the pathogenesis of B-cell lymphomas. We also summarize the role MYC plays in the diagnosis, prognostication and various strategies to detect MYC rearrangement and expression.
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Affiliation(s)
- Qingqing Cai
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - L. Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xiaolu Xu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Ken H. Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas, USA
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16
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Montgomery ND, Fedoriw Y. Pathology consultation on intermediate-to-large B-cell lymphomas. Am J Clin Pathol 2014; 141:305-17. [PMID: 24515757 DOI: 10.1309/ajcp3cp6vfzjymtk] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVES Intermediate-to-large B-cell lymphomas represent a heterogeneous group of aggressive lesions frequently encountered in practice. The differential diagnosis includes the most common of all lymphomas, diffuse large B-cell lymphoma (DLBCL), as well as Burkitt lymphoma (BL), B-lymphoblastic lymphoma, and the blastoid variant of mantle cell lymphoma. In recent decades, gene expression profiling studies have clarified the biologic origins and features of these diseases. Moreover, clinically relevant subtypes of DLBCL have been identified, and a new category was defined: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL. Herein, we review the salient diagnostic features of the various entities within this differential diagnosis and provide a stepwise diagnostic approach for dealing with challenging cases. METHODS A case-based approach is used to highlight diagnostic dilemmas and clinical decision points within the differential diagnosis of intermediate-to-large B-cell lymphomas. RESULTS Based on the published literature and World Health Organization criteria, we suggest a diagnostic algorithm for appropriate classification of these lymphomas. CONCLUSIONS Correct classification of intermediate-to-large B-cell lymphomas is important, because prognosis and therapeutic approach vary for different tumors and tumor subclasses. Understanding both disease-specific criteria and pathologic features that influence clinical behavior within a category is imperative for evaluation of these lymphomas.
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Affiliation(s)
- Nathan D. Montgomery
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill
| | - Yuri Fedoriw
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill
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17
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A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 2014; 123:1187-98. [PMID: 24398325 DOI: 10.1182/blood-2013-06-507996] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.
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18
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Rebelo-Pontes HA, Abreu MCD, Guimarães DM, Fonseca FP, Andrade BABD, Almeida OPD, Pinto Júnior DDS, Corrêa-Pontes FS. Burkitt's lymphoma of the jaws in the Amazon region of Brazil. Med Oral Patol Oral Cir Bucal 2014; 19:e32-8. [PMID: 23986017 PMCID: PMC3909429 DOI: 10.4317/medoral.18936] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 02/25/2013] [Indexed: 12/24/2022] Open
Abstract
Objectives: To describe the clinicopathologic and immunohistochemical features of Burkitt’s lymphoma of the jaws in 7 patients of Northern Brazil.
Study Design: Clinical data concerning gender, age, affected site, clinical presentation, symptomatology and follow-up were collected from the clinical files. Histopathology was complemented with a broad immunohistochemical panel and in situ hybridization for Epstein-Barr virus (EBV).
Results: Most of the patients were infants and 5 out of 7 were males. The mandible was affected in 5 cases and all patients also presented abdominal involvement. All cases were positive for CD45, CD20, CD79a, CD10, Bcl-6 and EBV. Ki-67 proliferative index was approximately 100%. Six patients were treated with R-CHOP (Rituximab + Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone) chemotherapy, and 2 of these died of the disease. One young adult patient refused treatment and died 3 months after initial diagnosis.
Conclusions: Burkitt’s lymphoma of the jaws diagnosed in the Amazon region of Brazil present similar clinicopathologic features to those described in endemic areas of Africa, including EBV positivity.
Key words:Burkitt’s lymphoma, EBV, Brazil, Amazon region.
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Affiliation(s)
- Hélder-Antônio Rebelo-Pontes
- Service of Oral Pathology, João de Barros Barreto, University Hospital-Federal, University of Pará, Mundurucus street, n 4877, Zip Code: 66073-000, Belém-Pará-Brazil,
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19
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Muñoz-Mármol AM, Sanz C, Tapia G, Marginet R, Ariza A, Mate JL. MYCstatus determination in aggressive B-cell lymphoma: the impact of FISH probe selection. Histopathology 2013; 63:418-24. [DOI: 10.1111/his.12178] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 04/30/2013] [Indexed: 11/29/2022]
Affiliation(s)
- Ana M Muñoz-Mármol
- Department of Pathology; Hospital Universitari Germans Trias i Pujol; Badalona; Barcelona; Spain
| | | | | | - Ruth Marginet
- Department of Pathology; Hospital Universitari Germans Trias i Pujol; Badalona; Barcelona; Spain
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20
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Sagaert X, Tousseyn T, Yantiss RK. Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology. World J Gastrointest Oncol 2012; 4:238-49. [PMID: 23443141 PMCID: PMC3581849 DOI: 10.4251/wjgo.v4.i12.238] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 08/29/2012] [Accepted: 11/20/2012] [Indexed: 02/05/2023] Open
Abstract
The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.
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Affiliation(s)
- Xavier Sagaert
- Xavier Sagaert, Thomas Tousseyn, Department of Pathology University Hospitals Leuven, B-3000 Leuven, Belgium
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21
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Frick M, Dörken B, Lenz G. New insights into the biology of molecular subtypes of diffuse large B-cell lymphoma and Burkitt lymphoma. Best Pract Res Clin Haematol 2012; 25:3-12. [DOI: 10.1016/j.beha.2012.01.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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22
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Abstract
For the past 20 years most malignant lymphomas have been classified as clinicopathological entities, each with its own combination of clinical, morphological, immunophenotypic and molecular genetic characteristics. Molecular and cytogenetic abnormalities can be detected by a wide range of techniques, ranging from conventional karyotyping to single nucleotide polymorphism analysis. In this review, we consider the common genetic abnormalities found in lymphoma and discuss the advantages and disadvantages of individual techniques used in their detection. Finally, we discuss briefly possible novel developments in the field of lymphoma diagnostics.
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Affiliation(s)
- Philip Kluin
- Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
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23
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Hwang CK, Melson MR, Grossniklaus HE. Diffuse large B cell lymphoma of the eyelid in a patient with AIDS. Br J Ophthalmol 2011; 95:739-40; quiz 740, 754. [PMID: 20675727 DOI: 10.1136/bjo.2009.163121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Christopher K Hwang
- Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA
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24
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Bellan C, Stefano L, Giulia DF, Rogena EA, Lorenzo L. Burkitt lymphoma versus diffuse large B-cell lymphoma: a practical approach. Hematol Oncol 2010; 28:53-6. [PMID: 19844983 DOI: 10.1002/hon.916] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Burkitt Lymphoma (BL) is listed in the World Health Organization (WHO) classification of lymphoid tumours as an 'aggressive B-cell non-Hodgkin's lymphoma', characterized by a high degree of proliferation of the malignant cells and deregulation of the c-MYC gene. The main diagnostic challenge in BL is to distinguish it from diffuse large B-cell lymphoma (DLBCL). While in children BL and DLBCL types probably do not differ clinically, and the differential diagnosis between BL and DLBCL may theoretically appear clear-cut, in adults daily practice shows the existence of cases that have morphological features, immunophenotypic and cytogenetics intermediate between DLBCL and BL, and cannot be classified with certainty in these categories. Distinguishing between BL and DLBCL is critical, as the two diseases require different management. This review summarizes the current practical approach, including the use of a large panel of antibodies, and cytogenetic and molecular diagnostic techniques, to distinguish between BL, DLBCL and the provisional category of 'B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma', now listed in the updated WHO classification.
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Affiliation(s)
- Cristiana Bellan
- Department of Human Pathology and Oncology, University of Siena, Siena, Italy
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25
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Quintanilla-Martinez L, de Jong D, de Mascarel A, Hsi ED, Kluin P, Natkunam Y, Parrens M, Pileri S, Ott G. Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XIV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France. J Hematop 2009; 2:211-36. [PMID: 20309430 PMCID: PMC2798939 DOI: 10.1007/s12308-009-0053-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2009] [Accepted: 12/01/2009] [Indexed: 12/16/2022] Open
Abstract
The term "gray-zone" lymphoma has been used to denote a group of lymphomas with overlapping histological, biological, and clinical features between various types of lymphomas. It has been used in the context of Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), including classical HL (CHL), and primary mediastinal large B cell lymphoma, cases with overlapping features between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B cell lymphoma, CHL, and Epstein-Barr-virus-positive lymphoproliferative disorders, and peripheral T cell lymphomas simulating CHL. A second group of gray-zone lymphomas includes B cell NHL with intermediate features between diffuse large B cell lymphoma and classical Burkitt lymphoma. In order to review controversial issues in gray-zone lymphomas, a joint Workshop of the European Association for Hematopathology and the Society for Hematopathology was held in Bordeaux, France, in September 2008. The panel members reviewed and discussed 145 submitted cases and reached consensus diagnoses. This Workshop summary is focused on the most controversial aspects of gray-zone lymphomas and describes the panel's proposals regarding diagnostic criteria, terminology, and new prognostic and diagnostic parameters.
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Affiliation(s)
- Leticia Quintanilla-Martinez
- Institute of Pathology, Eberhard-Karls-University of Tübingen, Tübingen, Germany
- Institute of Pathology, University Hospital Tübingen, Liebermeisterstr. 8, 72076 Tübingen, Germany
| | - Daphne de Jong
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Antoine de Mascarel
- Department of Pathology, CHU de Bordeaux, Hospital Haut-Lévêque, University of Bordeaux, Bordeaux, France
| | - Eric D. Hsi
- Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH USA
| | - Philip Kluin
- Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Yaso Natkunam
- Department of Pathology, Stanford University School of Medicine, Stanford, CA USA
| | - Marie Parrens
- Department of Pathology, CHU de Bordeaux, Hospital Haut-Lévêque, University of Bordeaux, Bordeaux, France
| | - Stefano Pileri
- Hematopathology Section, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Hospital, and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany
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26
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Bellan C, Stefano L, Giulia DF, Rogena EA, Lorenzo L. Burkitt lymphoma versus diffuse large B-cell lymphoma: a practical approach. Hematol Oncol 2009; 27:182-5. [PMID: 19670467 DOI: 10.1002/hon.914] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Burkitt Lymphoma (BL) is listed in the World Health Organization (WHO) classification of lymphoid tumours as an "aggressive B-cell non-Hodgkin's lymphoma", characterized by a high degree of proliferation of the malignant cells and deregulation of the c-MYC gene. The main diagnostic challenge in BL is to distinguish it from diffuse large B-cell lymphoma (DLBCL). While in children BL and DLBCL types probably do not differ clinically, and the differential diagnosis between BL and DLBCL may theoretically appear clear-cut, in adults daily practice shows the existence of cases that have morphological features, immunophenotypic and cytogenetics intermediate between DLBCL and BL, and cannot be classified with certainty in these categories. Distinguishing between BL and DLBCL is critical, as the two diseases require different management. This review summarizes the current practical approach, including the use of a large panel of antibodies, and cytogenetic and molecular diagnostic techniques, to distinguish between BL, DLBCL and the provisional category of "B-cell lymphoma, unclassificable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma", now listed in the updated WHO classification.
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Affiliation(s)
- Cristiana Bellan
- Department of Human Pathology and Oncology, University of Siena, Siena, Italy
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27
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Nelson M, Perkins SL, Dave BJ, Coccia PF, Bridge JA, Lyden ER, Heerema NA, Lones MA, Harrison L, Cairo MS, Sanger WG. An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 2009; 148:600-10. [PMID: 19895612 DOI: 10.1111/j.1365-2141.2009.07967.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Burkitt lymphoma (BL), an aggressive B-cell malignancy, is often curable with short intensive treatment regiments. Nearly all BLs contain rearrangements of the MYC/8q24 region; however, recent cytogenetic studies suggest that certain secondary chromosomal aberrations in BL correlate with an adverse prognosis. In this multi-centre study, the frequency and impact on clinical outcome of del(13q) and +7 in addition to MYC rearrangements as detected by fluorescence in situ hybridization (FISH) in children and adolescents with intermediate and high-risk BL registered on Children's Cancer Group study CCG-5961 were investigated. Analysis with 13q14.3 and 13q34 loci specific probes demonstrated deletions of 13q in 38/90 (42%) cases. The loss of either 13q14.3 or 13q34 alone occurred in 14% and 8% respectively, while 20% exhibited loss of both regions. Gain of chromosome 7 was observed in 7/68 (10%) cases and MYC rearrangements were detected in 84/90 (93%). Prognostic analysis controlling for known risk factors demonstrated that patients exhibiting loss of 13q, particularly 13q14.3, had a significant decrease in 5-year overall survival (77% vs. 95%, P = 0.012). These observations indicate that del(13q) occurs in childhood BL at frequencies higher than previously detected by classical cytogenetics and underscores the importance of molecular cytogenetics in risk stratification.
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Affiliation(s)
- Marilu Nelson
- Human Genetics Laboratories, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, 985440 Nebraska Medical Center, Omaha, NE 68198, USA
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28
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Jevremovic D, Viswanatha DS. Molecular diagnosis of hematopoietic and lymphoid neoplasms. Hematol Oncol Clin North Am 2009; 23:903-33. [PMID: 19577174 DOI: 10.1016/j.hoc.2009.04.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
This chapter summarizes the significance and molecular diagnostic detection of genetic abnormalities commonly associated with hematolymphoid neoplasms. Methodologic aspects of laboratory diagnosis are presented, as well as discussion of multiparameter genotyping of tumors for prognosis and the role of minimal residual disease monitoring in specific neoplasms.
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Affiliation(s)
- Dragan Jevremovic
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
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29
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Leucci E, Cocco M, Onnis A, De Falco G, van Cleef P, Bellan C, van Rijk A, Nyagol J, Byakika B, Lazzi S, Tosi P, van Krieken H, Leoncini L. MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation. J Pathol 2008; 216:440-50. [PMID: 18802929 DOI: 10.1002/path.2410] [Citation(s) in RCA: 141] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus.
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Affiliation(s)
- E Leucci
- Department of Human Pathology and Oncology, University of Siena, Italy
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Queiroga EM, Gualco G, Weiss LM, Dittmer DP, Araujo I, Klumb CE, Harrington WJ, Bacchi CE. Burkitt lymphoma in Brazil is characterized by geographically distinct clinicopathologic features. Am J Clin Pathol 2008; 130:946-56. [PMID: 19019773 DOI: 10.1309/ajcp64yohawlumpk] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with a consistent MYC translocation. Epstein-Barr virus (EBV) has been associated with BL at different frequencies, depending on the clinical variant and geographic regions. This is a large-scale study of BL in Brazil, including 234 patients from 5 geographic regions that are widely disparate socioeconomically, including pediatric (61.1%) and adult (37.6%) populations. EBV was present in 52.6% of all BL cases, varying from 29% (12/42) in the South to 76% (13/17) in the North. Most of the cases were EBV type A. The frequency was higher in the pediatric group, and EBV association within this age range predominated in all regions except the South. Expression of p53 protein was observed in 16.2%, and only rare cases showed p63 expression. BL in Brazil is regionally distinct and has a low incidence of p53 overexpression and a higher-than-expected association with EBV in sporadic cases.
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Theodosiou Z, Kasampalidis IN, Karayannopoulou G, Kostopoulos I, Bobos M, Bevilacqua G, Aretini P, Starita A, Lyroudia K, Pitas I. Evaluation of FISH image analysis system on assessing HER2 amplification in breast carcinoma cases. Breast 2007; 17:80-4. [PMID: 17889539 DOI: 10.1016/j.breast.2007.07.041] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2006] [Revised: 05/30/2007] [Accepted: 07/12/2007] [Indexed: 10/22/2022] Open
Abstract
HER2-positive breast cancer is characterized by aggressive growth and poor prognosis. Women with metastatic breast cancer with over-expression of HER2 protein or excessive presence of HER2 gene copies are potential candidates for Herceptin (Trastuzumab) targeted treatment that binds to HER2 receptors on tumor cells and inhibits tumor cell growth. Fluorescence in situ hybridization (FISH) is one of the most widely used methods to determine HER2 status. Typically, evaluation of FISH images involves manual counting of FISH signals in multiple images, a time consuming and error prone procedure. Recently, we developed novel software for the automated evaluation of FISH images and, in this study, we present the first testing of this software on images from two separate research clinics. To our knowledge, this is the first concurrent evaluation of any FISH image analysis software in two different clinics. The evaluation shows that the developed FISH image analysis software can accelerate evaluation of HER2 status in most breast cancer cases.
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Affiliation(s)
- Zenonas Theodosiou
- Department of Informatics, Aristotle University of Thessaloniki, Box 451, 54124 Thessaloniki, Greece
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Kaul P, Javangula K. Burkitt lymphoma masquerading as cardiac tamponade. J Cardiothorac Surg 2007; 2:30. [PMID: 17615068 PMCID: PMC1934902 DOI: 10.1186/1749-8090-2-30] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Accepted: 07/05/2007] [Indexed: 01/06/2023] Open
Abstract
A 61 year old man presented with diffuse large B cell lymphoma of the skin of the back of the shoulder which was excised and treated with chemotherapy (CHOP regime) in 1998. He was in complete remission till he presented in 2002 with extranodal marginal zone lymphoma of the parotid gland for which he underwent superficial parotidectomy and radiotherapy. He continued in remission till 2006 when he presented with recurrent pericardial effusion and tamponade. At median sternotomy, pericardial effusion was drained, an anterior pericardiectomy was done and a left posterior pericardial window made, and an enlarged hard paraaortic lymph node excised. Histology, immunocytochemistry and chromosome analysis revealed Burkitt lymphoma. Patient underwent chemotherapy with CODOX-M regime and continues in remission. This report is unusual on account of the highly atypical presentation of Burkitt lymphoma as cardiac tamponade, only a few cases having been reported previously, the occurrence of three lymphomas of different pathological and genomic profiles in one patient over a period of eight years and the relatively slow rate of growth of an otherwise fulminant tumour with high tumour doubling time. A review of literature with special emphasis on chromosomal diagnosis, transformation of other lymphomas into Burkitt lymphoma and mediastinal and cardiac involvement with Burkitt lymphoma is presented.
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Affiliation(s)
- Pankaj Kaul
- Department of Cardiothoracic Surgery, Yorkshire Heart Centre, Leeds General Infirmary, Great George Street, Leeds, LSI 3EX, UK
| | - Kalyana Javangula
- Department of Cardiothoracic Surgery, Yorkshire Heart Centre, Leeds General Infirmary, Great George Street, Leeds, LSI 3EX, UK
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Guikema JEJ, de Boer C, Haralambieva E, Smit LA, van Noesel CJM, Schuuring E, Kluin PM. IGH switch breakpoints in Burkitt lymphoma: exclusive involvement of noncanonical class switch recombination. Genes Chromosomes Cancer 2006; 45:808-19. [PMID: 16736499 DOI: 10.1002/gcc.20345] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Most chromosomal t(8;14) translocations in sporadic Burkitt lymphomas (BL) are mediated by immunoglobulin class switch recombination (CSR), yet all tumors express IgM, suggesting an incomplete or exclusively monoallelic CSR event. We studied the exact configuration of both the nontranslocated IGH allele and the MYC/IGH breakpoint by applying a combination of low- and high-resolution methods (interphase FISH, DNA fiber FISH, long-distance PCR, and Southern blotting) on 16 BL. IGH class switch events involving the nontranslocated IGH allele were not observed. Thirteen cases had MYC/IGH breakpoints in or nearby IGH switch (S) sites, including five at Smu, three at Sgamma and five at Salpha. All eight translocations with a breakpoint at Sgamma or Salpha were perfectly reciprocal, without deletion of Cmu-Cdelta or other CH elements. Internal Smu deletions claimed to be a marker for CSR activity and implicated in stabilization of IgM expression were found in BL but did not correlate with downstream translocation events. This study shows that switch breakpoints in sporadic BL are exclusively resolved by a noncanonical recombination mechanism involving only one switch region.
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Affiliation(s)
- Jeroen E J Guikema
- Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
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Ventura RA, Martin-Subero JI, Jones M, McParland J, Gesk S, Mason DY, Siebert R. FISH analysis for the detection of lymphoma-associated chromosomal abnormalities in routine paraffin-embedded tissue. J Mol Diagn 2006; 8:141-51. [PMID: 16645199 PMCID: PMC1867591 DOI: 10.2353/jmoldx.2006.050083] [Citation(s) in RCA: 232] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Over the last decade, fluorescence in situ hybridization (FISH) has become a firmly established technique in the diagnosis and assessment of lymphoid malignancies. However, this technique is not wide-ly used in the routine diagnostic evaluation of paraffin-embedded biopsies, most likely because of a perception that it is technically more demanding. There are also uncertainties regarding diagnostic thresholds and the way in which results should be interpreted. In this Review, we describe practical strategies for using FISH analysis to detect lymphoma-associated chromosomal abnormalities in routine paraffin-embedded lymphoma biopsies. Furthermore, we provide proposals on how FISH results should be interpreted (including how to calculate cutoff levels for FISH probes), recorded, and reported. An online appendix (available at http://jmd.amjpathol.org) details various simple, yet robust procedures for paraffin FISH analysis; it also provides additional information on the production of FISH probes, evaluating and reporting FISH results, sources for reagents and equipment, and troubleshooting. We hope that these suggestions will make FISH technology for the study of lymphoma biopsies more accessible to routine diagnostic and research laboratories.
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Affiliation(s)
- Roland A Ventura
- LRF Immunodiagnostics Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, United Kingdom
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36
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Einerson RR, Law ME, Blair HE, Kurtin PJ, McClure RF, Ketterling RP, Flynn HC, Dogan A, Remstein ED. Novel FISH probes designed to detect IGK-MYC and IGL-MYC rearrangements in B-cell lineage malignancy identify a new breakpoint cluster region designated BVR2. Leukemia 2006; 20:1790-9. [PMID: 16888615 DOI: 10.1038/sj.leu.2404340] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Detection of translocations involving MYC at 8q24.1 in B-cell lineage malignancies (BCL) is important for diagnostic and prognostic purposes. However, routine detection of MYC translocations is often hampered by the wide variation in breakpoint location within the MYC region, particularly when a gene other than IGH, such as IGK or IGL, is involved. To address this issue, we developed and validated four fluorescence in situ hybridization (FISH) probes: two break apart probes to detect IGK and IGL translocations, and two dual-color, dual-fusion FISH (D-FISH) probes to detect IGK-MYC and IGL-MYC. MYC rearrangements (four IGK-MYC, 12 IGL-MYC and four unknown partner gene-MYC) were correctly identified in 20 of 20 archival BCL specimens known to have MYC rearrangements not involving IGH. Seven specimens, all of which lacked MYC rearrangements using a commercial IGH/MYC D-FISH probe, were found to have 8q24 breakpoints within a cluster region >350-645 kb 3' from MYC, provisionally designated as Burkitt variant rearrangement region 2 (BVR2). FISH is a useful ancillary tool in identifying MYC rearrangements. In light of the discovery of the distally located BVR2 breakpoint cluster region, it is important to use MYC FISH probes that cover a breakpoint region at least 1.0 Mb 3' of MYC.
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Affiliation(s)
- R R Einerson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
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37
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Kostopoulos I, Cocco M, Ginanneschi C, D'Amuri A, Lazzi S, Fabbri A, Forconi F, De Santi MM, Leoncini L. Overlapping morphologic and immunophenotypic profiles in small B-cell lymphoma. A report of two cases. Virchows Arch 2006; 449:320-7. [PMID: 16847683 DOI: 10.1007/s00428-006-0242-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2006] [Accepted: 05/31/2006] [Indexed: 11/24/2022]
Abstract
We present two cases of small B-cell lymphomas of particular diagnostic interest because the histological patterns were at variance with their immunophenotype. One of these lymphomas, involving the gallbladder and duodenum, showed a marginal zone lymphoma-like (MALT type) pattern of cellular infiltration with CD5 negativity but (unexpectedly) Cyclin D1 positivity. Fluorescence in situ hybridization analysis of this case was performed because of the aberrant expression of Cyclin D1, and was clearly positive for the Cyclin D1 gene translocation. The second case, occurring in a lymph node, showed the typical growth pattern of a follicular lymphoma but it had an atypical immunophenotype, namely, expression of Cyclin D1, CD10, and Bcl2 and focally Bcl6, accompanied by a lack of CD5 and CD23. The Cyclin D1 gene translocation was detected by fluorescence in situ hybridisation (FISH), whereas c-myc and Bcl2 genes translocation were absent. Numerical chromosomal changes, which were visualized for chromosomes 8, 11, and 18 could be correlated to the aberrant immunoprofile. In this context, we discuss the diagnostic value of Cyclin D1, CD5, CD23, CD10, Bcl6 markers revealed by immunohistochemistry, as well as the significance of detection by FISH of chromosomal translocations such as t(11;14) and t(14;18). The question still remains as to whether such cases should be designated as specific lymphoma entities or reported as unclassifiable and the chromosome aberration reported.
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MESH Headings
- Aged
- B-Lymphocytes/metabolism
- B-Lymphocytes/pathology
- Biomarkers, Tumor/metabolism
- Chromosomes, Human, Pair 11/genetics
- Chromosomes, Human, Pair 14/genetics
- Chromosomes, Human, Pair 18/genetics
- Chromosomes, Human, Pair 8/genetics
- Cyclin D1/genetics
- Cyclin D1/metabolism
- Female
- Humans
- Immunophenotyping/methods
- In Situ Hybridization, Fluorescence
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Lymph Nodes/metabolism
- Lymph Nodes/pathology
- Male
- Middle Aged
- Translocation, Genetic
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Affiliation(s)
- Ioannis Kostopoulos
- Department of Pathology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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38
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Bosga-Bouwer AG, van den Berg A, Haralambieva E, de Jong D, Boonstra R, Kluin P, van den Berg E, Poppema S. Molecular, cytogenetic, and immunophenotypic characterization of follicular lymphoma grade 3B; a separate entity or part of the spectrum of diffuse large B-cell lymphoma or follicular lymphoma? Hum Pathol 2006; 37:528-33. [PMID: 16647949 DOI: 10.1016/j.humpath.2005.12.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2005] [Revised: 12/06/2005] [Accepted: 12/15/2005] [Indexed: 11/17/2022]
Abstract
We studied a histological homogeneous group of 29 cases with the diagnosis of follicular lymphoma (FL) grade 3B (FL3Bs). In a previous study, we subdivided this group in 3 subgroups based on (1) aberrations of the 3q27 region, (2) lack of 3q27 and t(14;18), and (3) the presence of a t(14;18). In this study, we further characterized the FL3B lymphomas that are currently part of the spectrum of FL in the WHO classification, taking into account other cytogenetical aberrations, immunohistochemistry for P53, bcl2, bcl6, and CD10, rearrangement of the proto-oncogene myc, and mutation of the tumor suppressor gene TP53. With respect to P53, bcl2, bcl6 expression, myc rearrangement, and TP53 mutation, FL3B represents a homogeneous group. CD10 expression and gain of chromosome 7, considered to be typical FL markers, were more common in the FL3B t(14;18)-positive subgroup. The lack of CD10 expression and gain of chromosome 7 in most cases in the other 2 subgroups suggest that those cases have a closer relation to diffuse large B-cell lymphomas.
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MESH Headings
- Biomarkers, Tumor/analysis
- DNA Mutational Analysis
- DNA, Neoplasm/analysis
- Genes, myc
- Genes, p53
- Humans
- Immunohistochemistry
- Immunophenotyping
- In Situ Hybridization, Fluorescence
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/pathology
- Lymphoma, Follicular/chemistry
- Lymphoma, Follicular/genetics
- Lymphoma, Follicular/pathology
- Lymphoma, Large B-Cell, Diffuse/chemistry
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Mutation
- Proto-Oncogene Mas
- Proto-Oncogene Proteins c-bcl-2/analysis
- Proto-Oncogene Proteins c-bcl-6/analysis
- Tumor Suppressor Protein p53/analysis
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Affiliation(s)
- Anneke G Bosga-Bouwer
- Department of Medical Genetics, University Medical Center Groningen, and University of Groningen, 9713AW Groningen, The Netherlands.
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Kluiver J, Haralambieva E, de Jong D, Blokzijl T, Jacobs S, Kroesen BJ, Poppema S, van den Berg A. Lack of BIC and microRNA miR-155 expression in primary cases of Burkitt lymphoma. Genes Chromosomes Cancer 2006; 45:147-53. [PMID: 16235244 DOI: 10.1002/gcc.20273] [Citation(s) in RCA: 182] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
We previously demonstrated high expression of primary-microRNA BIC (pri-miR-155) in Hodgkin lymphoma (HL) and lack of expression in most non-Hodgkin lymphoma subtypes including some Burkitt lymphoma (BL) cases. Recently, high expression of BIC was reported in BL in comparison to pediatric leukemia and normal peripheral-blood samples. In this study, we extended our series of BL cases and cell lines to examine expression of BIC using RNA in situ hybridization (ISH) and quantitative RT-PCR (qRT-PCR) and of miR-155 using Northern blotting. Both BIC RNA ISH and qRT-PCR revealed no or low levels of BIC in 25 BL tissue samples [including 7 Epstein-Barr virus (EBV)-positive cases] compared to HL and normal controls. In agreement with these findings, no miR-155 was observed in BL tissues. EBV-negative and EBV latency type I BL cell lines also showed very low BIC and miR-155 expression levels as compared to HL cell lines. Higher levels of BIC and miR-155 were detected in in vitro transformed lymphoblastoid EBV latency type III BL cell lines. An association of latency type III infection and induction of BIC was supported by consistent expression of BIC in 11 and miR-155 in 2 posttransplantation lymphoproliferative disorder (PTLD) cases. In summary, we demonstrated that expression of BIC and miR-155 is not a common finding in BL. Expression of BIC and miR-155 in 3 latency type III EBV-positive BL cell lines and in all primary PTLD cases suggests a possible role for EBV latency type III specific proteins in the induction of BIC expression.
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Affiliation(s)
- Joost Kluiver
- Department of Pathology & Laboratory Medicine, Groningen University Medical Center, The Netherlands
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40
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Fenton JAL, Schuuring E, Barrans SL, Banham AH, Rollinson SJ, Morgan GJ, Jack AS, van Krieken JHJM, Kluin PM. t(3;14)(p14;q32) results in aberrant expression of FOXP1 in a case of diffuse large B-cell lymphoma. Genes Chromosomes Cancer 2006; 45:164-8. [PMID: 16252263 DOI: 10.1002/gcc.20278] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Strong expression of Forkhead box-P1 (FOXP1), a winged-helix transcription factor, has been identified as an independent prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, possible mechanisms of deregulation of this gene, on 3p14.1, have yet to be elucidated. We have identified a breakpoint at the IGA1 gene in the immunoglobulin heavy chain (IGH) locus at 14q32 that was juxtaposed to the FOXP1 gene locus in a gastric DLBCL that showed strong expression of FOXP1. This may be one possible mechanism of deregulating FOXP1 expression by placing it under the control of IGH enhancers.
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Affiliation(s)
- James A L Fenton
- Department of Haematological Oncology, University of Leeds, United Kingdom.
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Abstract
This review will focus on the molecular biology of lymphoproliferative disorders with emphasis on lymphomas. The spectrum of known recurrent gene rearrangements found in lymphomas will be outlined and their relevance to diagnosis and subclassification of disease will be discussed. Finally, a survey of the current trends in gene expression profiling of lymphomas by microarray technology will be presented with reference to implications for diagnosis, classification, prognosis and treatment.
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Affiliation(s)
- Alberto Catalano
- Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
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42
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Clinical, Immunophenotypic, and Genetic Analysis of Adult Lymphomas With Morphologic Features of Burkitt Lymphoma. Am J Surg Pathol 2005. [DOI: 10.1097/01.pas.0000168176.71405.e5] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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van Imhoff GW, van der Holt B, MacKenzie MA, Ossenkoppele GJ, Wijermans PW, Kramer MHH, van 't Veer MB, Schouten HC, van Marwijk Kooy M, van Oers MHJ, Raemaekers JMM, Sonneveld P, Meulendijks LAMH, Kluin PM, Kluin-Nelemans HC, Verdonck LF. Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma. Leukemia 2005; 19:945-52. [PMID: 15800666 DOI: 10.1038/sj.leu.2403733] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.
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Affiliation(s)
- G W van Imhoff
- Department of Hematology, University Medical Center Groningen, 97 RB Groningen, The Netherlands.
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Boerma EG, van Imhoff GW, Appel IM, Veeger NJGM, Kluin PM, Kluin-Nelemans JC. Gender and age-related differences in Burkitt lymphoma--epidemiological and clinical data from The Netherlands. Eur J Cancer 2005; 40:2781-7. [PMID: 15571961 DOI: 10.1016/j.ejca.2004.09.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2004] [Revised: 07/27/2004] [Accepted: 09/03/2004] [Indexed: 11/21/2022]
Abstract
Although Burkitt's lymphoma (BL) is classified as one entity in the World Health Organisation (WHO) classification, we wondered whether BL should not be considered as a different disease in children compared with adults. Netherlands Cancer Registry (NCR) data were obtained from 1994 to 1998 (n=203). Detailed clinical data from two treatment protocols were compared: one for adults up to the age of 65 years (n=27) and one for children (n=80). All slides of the two clinical studies were centrally reviewed which included immunophenotyping and when necessary breakpoint analysis of MYC/8q24. Only cases with an unambiguous diagnosis of BL (classical and atypical BL) were accepted. The age distribution of BL-patients showed a bimodal distribution with a peak at the paediatric age and a steady increase after approximately 60 years of age. Most of the patients were males (89% for children and 78% for adults) and only male patients showed this bimodality. Children more often had extranodal disease (81% vs. 59%), whereas adults more often had nodal disease (89% vs. 53%). Based on epidemiology and clinical presentation, the concept that BL is one disease should be re-challenged.
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Affiliation(s)
- E G Boerma
- Department of Haematology, Groningen University Medical Centre, The Netherlands.
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45
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Guikema JEJ, Fenton JAL, de Boer C, Kleiverda K, Brink AATP, Raap AK, Estrov Z, Schuuring E, Kluin PM. Complex biallelicIGH rearrangements in IgM-expressing Z-138 cell line: Involvement of downstream immunoglobulin class switch recombination. Genes Chromosomes Cancer 2005; 42:164-9. [PMID: 15543623 DOI: 10.1002/gcc.20132] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Chromosomal translocations involving the immunoglobulin (Ig) receptor loci usually disrupt and silence these loci. On the basis of observations in follicular lymphoma (FL) with downstream Ig heavy chain (IGH) class switch recombination (CSR), we hypothesized that downstream CSR-mediated chromosomal translocations would leave the V(D)J-Cmu transcription unit intact, thereby still allowing IgM expression from the IGH allele involved in the translocation. To test this hypothesis, we analyzed biallelic IGH translocations in the IgM-expressing cell line Z-138 by interphase FISH, DNA fiber-FISH, long-distance vectorette PCR, and DNA sequencing. One IGH allele was involved in a t(11;14), showing a break in the JH region that juxtaposed the Emu enhancer and the 3' Calpha enhancers to the cyclin D1 gene. The other IGH allele contained a t(8;14) breakpoint involving the 3' end of a Sgamma region, whereas the reciprocal breakpoint at 8q24 was approximately 40 kb centromeric of MYC. Molecular analysis showed that this IGH allele harbored a normal V(D)J-Cmu complex, which is responsible for IgM expression. These data show that chromosomal breakpoints such as the t(8;14) can occur in downstream IGH constant regions and do not necessarily interfere with Ig expression.
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Affiliation(s)
- Jeroen E J Guikema
- Department of Pathology and Laboratory Medicine, Groningen University Medical Center, Groningen, The Netherlands.
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46
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Place de la FISH interphasique dans le diagnostic des lymphomes. Ann Pathol 2004. [DOI: 10.1016/s0242-6498(04)94059-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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47
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Ferber MJ, Eilers P, Schuuring E, Fenton JAL, Fleuren GJ, Kenter G, Szuhai K, Smith DI, Raap AK, Brink AATP. Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papillomavirus integration cluster in FRA8C at 8q24.13. ACTA ACUST UNITED AC 2004; 154:1-9. [PMID: 15381365 DOI: 10.1016/j.cancergencyto.2004.01.028] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2003] [Revised: 01/20/2004] [Accepted: 01/28/2004] [Indexed: 10/26/2022]
Abstract
Molecular cytogenetic analysis frequently shows human papillomavirus (HPV) integration near translocation breakpoints in cervical cancer cells. We have recently described a cluster of HPV18 integrations in the distal end of the common fragile site FRA8C at 8q24 in primary cervical carcinoma samples. Chromosome band 8q24 contains the MYC gene (alias c-MYC), FRA8C, and FRA8D. The MYC gene is frequently deregulated--usually by translocation or amplification--in various tumor types. In the present study, we performed a molecular cytogenetic analysis of HPV18 integration patterns and the 8q24 translocation in a primary cervical carcinoma and in HeLa cells using combined binary ratio-fluorescence in situ hybridization. Our aim was to determine how the chromosomal breaks involved in these events relate physically to the MYC gene; whether they map to the FRA8C site, the FRA8D site, or both; and how they correlate with the occurrence of DNA flexibility domains. The 8q24 translocation breakpoints mapped between stretches of integrated HPV18 sequences in the distal end of FRA8C. This region contained DNA helix flexibility clusters, several of which mapped in the vicinity of HPV integration sites and translocation breakpoints in cervical carcinomas. DNA helix flexibility clusters were also found near known MYC translocation breakpoints in Burkitt lymphomas (BL), but most BL breakpoints mapped clearly outside FRA8C. Our data revealed that FRA8C is involved in HPV integration and chromosomal translocations in cervical carcinoma; however, this fragile site is not involved in classical MYC translocations in most BLs. In the context of the familial nature of cervical cancer, FRA8C may be considered a candidate susceptibility region for cervical carcinoma.
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Affiliation(s)
- Matthew J Ferber
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
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