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Burkitt-Like Lymphoma with 11Q Aberration: a Ferrata Storti Foundation Germinal Center-Derived Lymphoma Genetically Unrelated to Burkitt Lymphoma

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Burkitt-Like Lymphoma with 11Q Aberration: a Ferrata Storti Foundation Germinal Center-Derived Lymphoma Genetically Unrelated to Burkitt Lymphoma ARTICLE Non-Hodgkin Lymphoma Burkitt-like lymphoma with 11q aberration: a Ferrata Storti Foundation germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma Blanca Gonzalez-Farre,1,2,3* Joan Enric Ramis-Zaldivar,2,3* Julia Salmeron- Villalobos,2 Olga Balagué,1,2,3 Verónica Celis,4 Jaime Verdu-Amoros,5 Ferran Nadeu,2,3 Constantino Sábado,6 Antonio Ferrández,7 Marta Garrido,8 Federico García-Bragado,9 María Dolores de la Maya,10 José Manuel Vagace,10 Carlos Haematologica 2019 Manuel Panizo,11 Itziar Astigarraga,12 Mara Andrés,13 Elaine S. Jaffe,14 Elias Volume 104(9):1822-1829 Campo1,2,3* and Itziar Salaverria2,3* 1Hematopathology Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; 2Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; 4Pediatric Oncology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain; 5Pediatric Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; 6Pediatric Oncology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 7Pathology Department, Hospital Clínico de Valencia, Valencia, Spain; 8Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 9Pathology Department, Complejo Hospitalario de Navarra, Pamplona, Spain; 10Pediatric Hematology Department, Hospital Materno Infantil de Badajoz, Badajoz, Spain; 11Department of Hematology, Clínica Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 12Pediatrics Department, Hospital Universitario Cruces, IIS Biocruces Bizkaia, UPV/EHU, Barakaldo, Spain; 13Pediatric Oncology Department, Hospital La Fe, Valencia, Spain and 14Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA *BGF, JERZ, EC and IS contributed equally to this work. ABSTRACT urkitt-like lymphoma with 11q aberration is characterized by patho- Correspondence: logical features and gene expression profile resembling those of ITZIAR SALAVERRIA BBurkitt lymphoma but lacks the MYC rearrangement and carries an [email protected] 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized Received: October 5, 2018. entities is controversial. To improve the understanding of Burkitt-like lym- phoma with 11q aberration we performed an analysis of copy number Accepted: February 7, 2019. alterations and targeted sequencing of a large panel of B-cell lymphoma- Pre-published: February 7, 2019. related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma doi:10.3324/haematol.2018.207928 (2 cases) and only one was considered as atypical Burkitt lymphoma. All Check the online version for the most updated cases had a germinal center B-cell signature and phenotype with frequent information on this article, online supplements, LMO2 expression. The patients with Burkitt-like lymphoma with 11q aber- and information on authorship & disclosures: ration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and www.haematologica.org/content/104/9/1822 lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alter- ations. Potential driver mutations were found in 27 genes, particularly ©2019 Ferrata Storti Foundation involving BTG2, DDX3X, ETS1, EP300, and GNA13. However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of Burkitt-like lymphoma with 11q aberration is a germinal center-derived published material is allowed under the following terms and lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lym- conditions: phoma than to Burkitt lymphoma. https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: Introduction https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing Our knowledge of lymphomas in children and young adults has increased dramat- from the publisher. ically in the last years with the identification of several subtypes that predominantly occur in this age subgroup.1-4 One of these recently recognized categories is Burkitt- like lymphoma with 11q aberration (BLL-11q) which has morphological, phenotyp- 1822 haematologica | 2019; 104(9) Burkitt-like lymphoma with 11q aberration ic, and gene expression profiles resembling those of Burkitt per probe, while the pattern corresponding to the 11q lymphoma (BL), but lacks MYC rearrangements according gain/loss or gain/amplification/loss aberration would be to standard methods of detection, such as fluorescence in two blue, three up to five green signals and one red signal. situ hybridization (FISH). Alternatively, these tumors carry The probe was tested in an independent series of eight an 11q-arm aberration characterized by proximal gains and non-Hodgkin B-cell lymphomas and four MYC-negative telomeric losses.4 In comparison with BL, BLL-11q seems HGBCL with lack of the 11q alteration by array analysis to have more complex karyotypes, a certain degree of and all showed the normal pattern described above. cytological pleomorphism, sporadically a follicular pattern and a high incidence of nodal presentation.4,5 Very similar Copy number analysis cases have also been reported in the post-transplant set- DNA was hybridized on Oncoscan FFPE or SNP array platform ting,6 although its incidence in other immunocompromised (ThermoFisher Scientific, Waltham, MA, USA) and analyzed as conditions, such as human immunodeficiency infection, is described previously (Online Supplementary Methods).2 Published still unclear.7,8 copy number data on MYC-positive BL20 and DLBCL13 were rean- BLL-11q has been incorporated in the revised World alyzed for comparison. Health Organization (WHO) classification as a provisional category1 because its precise taxonomy as a particular vari- Sequencing approaches ant of BL, diffuse large B-cell lymphoma (DLBCL) or a dis- The mutational status of 96 B-cell lymphoma-related genes tinct form of high-grade B-cell lymphoma (HGBCL) is still (Online Supplementary Table S2) was examined by target next-gen- controversial.1,4-6,9-11 The clarification of the biological eration sequencing in ten BLL-11q cases and four MYC-negative nature of this uncommon subtype of lymphoma is clini- 11q-negative cases using a NGS SureSelect XT Target Enrichment cally relevant because of increasing interest in defining the System Capture strategy (Agilent Technologies, Santa Clara, CA, most appropriate management strategies for specific sub- USA) before sequencing in a MiSeq instrument (Illumina, San types of lymphomas in pediatric and young adult Diego, CA, USA) (Online Supplementary Methods). Additionally, patients.12 Recent DNA copy number alteration and next- analysis of hotspots of mutation in ID3, TCF3 and CCND3 genes, generation sequencing studies have provided a compre- ETS1 exon 1 (transcript NM_005238) and verification of variants hensive catalog of genomic aberrations in BL and DLBCL in specific cases was performed by Sanger sequencing using which clearly distinguish these entities.13-17 In this study primers described in Online Supplementary Table S3. we performed an integrated analysis of genomic and mutational alterations with a complete annotation of clin- Gene expression analysis ical and pathological features of BLL-11q with the goal of Cell of origin was determined by Lymph2Cx assay (Nanostring, obtaining insights to refine the understanding of the Seattle, WA, USA) as previously published.21 Gene expression lev- pathogenesis of these tumors and improve their diagnosis. els of MYC and ETS1 were investigated by real-time quantitative polymerase chain reaction (Online Supplementary Methods) using Taqman assays described in Online Supplementary Table S4. Methods Statistical methods 2 Sample selection and DNA/RNA extraction The χ method was used for categorical variables and Student t- To identify BLL-11q cases we initially reevaluated the presence tests for continuous variables. Non-parametric tests were applied of MYC translocations in 95 cases diagnosed as BL, atypical BL or when necessary. The P-values for multiple comparisons were HGBCL, not otherwise specified (NOS), in our Hematopathology adjusted using the Benjamini–Hochberg correction. Survival Unit between 2000-2016. Three consultation cases from centers curves were estimated with the Kaplan-Meier method. Statistical belonging to the Sociedad Española de Hematología y Oncología analyses were carried out with SPSS v22 and R software v3.1.3. Pediátricas (SEHOP) were also analyzed. Cases were reviewed by three pathologists (BG-F, EC, ESJ). DNA and RNA were extracted using standard protocols (Qiagen, Hilden, Germany). This study Results was approved by the Institutional Review Board of the Hospital Clinic of Barcelona. Informed consent was obtained from all Identification of cases with Burkitt-like lymphoma with patients in accordance
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