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High-resolution copy number analysis of paired normal-tumor samples from diffuse large B cell lymphoma

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Abstract

Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.

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Acknowledgments

We thank Alicia Antón, Montserrat Hernández-Ruano, Rebeca Maldonado, Alejandra Martín, and Ana Díaz (University Hospital of Salamanca, Salamanca, Spain); Eva García-García (Center of Cancer Research, Salamanca, Spain); and Mark Catherwood (Belfast City Hospital, Belfast, UK) for their technical support. We are grateful to José Ramón González-Porras, María Victoria Mateos, and Jesús Martín Sánchez for their intellectual and statistical support. We also thank all members of GELTAMO and the patients who participated in this study.

This work was supported by research funding from the Health Council of Castilla y León (GRS265/A/08), the Health Research Program (PS09/01382), and the Red Temática de Investigación Cooperativa en Cáncer (RTICC) grant RD12/0036 (groups 0069, 0029, 0036, 0058, and 0060) included in the National Plan I+D+I supported by the Instituto Carlos III and the Fondo Europeo de Desarrollo Regional (FEDER), the Spanish Ministry of Economy and Competitiveness, and the European Regional Development Fund (ERDF) “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010).

ES was supported by CM10/00078-Río Hortega, an ISCIII contract, FEHH grant 2013–2014 and JR14/00025-Juan Rodés, an ISCIII contract. IS was supported by the Subprograma Juan de la Cierva (JCI-2011-10232) and a Miguel Servet contract (CP13/00159).

Authors’ contributions

ES, MA, LM, MDC, RGS, and MG made the conception and design of the research. ES obtained molecular results, assisted by MA, AB, CJ, MG, NCG, and AA. MES, IP, and RC provided support for the molecular results. ES, IS, and DMG analyzed copy number data. MA provided support for data analysis. MSB performed the statistical analyses, assisted by DMG and ES. GP, LM, and MCC provided statistical support. EGB, EP, and MDC provided patient samples and/or clinical data. AC provided biological data. OB and SMM provided samples and performed the pathology review. ES wrote the first draft of the manuscript. IS reviewed the first version and rewrote it. ES, IS, DMG, MA, LM, RGS, and MG reviewed the final manuscript. MG, RGS, LM, and ES obtained the financial support for the study. MG was the head of the group. IS, RGS, and MG produced the final revision of the manuscript. All the authors read the manuscript and gave the final approval for publication.

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    Authors and Affiliations

    1. Molecular Biology & Histocompatibility Unit, Department of Hematology, IBSAL – University Hospital of Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain

      Elena Sebastián, Miguel Alcoceba, Ana Balanzategui, Luis Marín, Cristina Jiménez, María García-Álvarez, Norma C. Gutiérrez, M. Eugenia Sarasquete, Carmen Chillón, Rocío Corral, M. Isabel Prieto-Conde, M. Dolores Caballero, Ramón García-Sanz & Marcos González

    2. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

      Elena Sebastián, Miguel Alcoceba, Ana Balanzategui, Luis Marín, Norma C. Gutiérrez, M. Eugenia Sarasquete, Carmen Chillón, Rocío Corral, M. Dolores Caballero, Ramón García-Sanz & Marcos González

    3. Spanish Lymphoma/Autologous Bone Marrow Transplant Study Group (GELTAMO), Salamanca, Spain

      Elena Sebastián, Miguel Alcoceba, Santiago Montes-Moreno, Eva González-Barca, Emilia Pardal, M. Dolores Caballero & Ramón García-Sanz

    4. Hematopathology Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

      David Martín-García, Guillem Clot & Itziar Salaverria

    5. Department of Pathology, University Hospital of Salamanca, Salamanca, Spain

      Óscar Blanco

    6. Department of Statistics, University of Salamanca, Salamanca, Spain

      Mercedes Sanchez-Barba

    7. Department of Pathology, University Hospital of Marqués de Valdecilla/IFIMAV, Santander, Spain

      Santiago Montes-Moreno

    8. Fundación Pública Galega de Medicina Xenómica, IDIS, SERGAS, Santiago de Compostela, Spain

      Ángel Carracedo

    9. Grupo de Medicina Xenómica, CIBERER, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

      Ángel Carracedo

    10. Center for Cancer Research (CIC, IBMCC-USAL-CSIC), Salamanca, Spain

      Ramón García-Sanz & Marcos González

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    1. Elena Sebastián
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    Correspondence to Ramón García-Sanz.

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    Informed consent was provided by all participants. The study was performed in accordance with the Declaration of Helsinki and Spanish legislation. The study was approved by the local Ethics Review Committee.

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    Elena Sebastián, Miguel Alcoceba, David Martín-García, Itziar Salaverria, Ramón García-Sanz and Marcos González contributed equally to this work.

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    Sebastián, E., Alcoceba, M., Martín-García, D. et al. High-resolution copy number analysis of paired normal-tumor samples from diffuse large B cell lymphoma. Ann Hematol 95, 253–262 (2016). https://doi.org/10.1007/s00277-015-2552-3

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