Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Lymphoma

Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation

Leukemia volume 28, pages 1334–1340 (2014)Cite this article

Subjects

Abstract

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Schmid C, Kirkham N, Diss T, Isaacson PG . Splenic marginal zone cell lymphoma. Am J Surg Pathol 1992; 16: 455–466.

    CAS  PubMed  Google Scholar 

  2. Matutes E, Oscier D, Montalban C, Berger F, Callet-Bauchu E, Dogan A et al. Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia 2008; 22: 487–495.

    Article  CAS  PubMed  Google Scholar 

  3. Rinaldi A, Kwee I, Young KH, Zucca E, Gaidano G, Forconi F et al. Genome-wide high resolution DNA profiling of hairy cell leukaemia. Br J Haematol 2013; 162: 566–569.

    Article  CAS  PubMed  Google Scholar 

  4. Robledo C, Garcia JL, Benito R, Flores T, Mollejo M, Martinez-Climent JA et al. Molecular characterization of the region 7q22.1 in splenic marginal zone lymphomas. PLoS One 2011; 6: e24939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Arribas AJ, Gomez-Abad C, Sanchez-Beato M, Martinez N, Dilisio L, Casado F et al. Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling. Modern Pathol 2013; 26: 889–901.

    Article  CAS  Google Scholar 

  6. Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG, Chiang MY et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med 2012; 209: 1553–1565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med 2012; 209: 1537–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2008.

    Google Scholar 

  9. Marco-Sola S, Sammeth M, Guigo R, Ribeca P . The GEM mapper: fast, accurate and versatile alignment by filtration. Nat Methods 2012; 9: 1185–1188.

    Article  CAS  PubMed  Google Scholar 

  10. Homer N, Merriman B, Nelson SF . BFAST: an alignment tool for large scale genome resequencing. PLoS One 2009; 4: e7767.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009; 25: 2078–2079.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Derrien T, Estelle J, Marco Sola S, Knowles DG, Raineri E, Guigo R et al. Fast computation and applications of genome mappability. PLoS One 2012; 7: e30377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38: e164.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 2012; 6: 80–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29: 308–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA et al. A map of human genome variation from population-scale sequencing. Nature 2010; 467: 1061–1073.

    Article  PubMed  Google Scholar 

  17. Hampel F, Ehrenberg S, Hojer C, Draeseke A, Marschall-Schroter G, Kuhn R et al. CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling. Blood 2011; 118: 6321–6331.

    Article  CAS  PubMed  Google Scholar 

  18. Kuroda K, Han H, Tani S, Tanigaki K, Tun T, Furukawa T et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 2003; 18: 301–312.

    Article  CAS  PubMed  Google Scholar 

  19. Ayoub N, Noma K, Isaac S, Kahan T, Grewal SI, Cohen A . A novel jmjC domain protein modulates heterochromatization in fission yeast. Mol Cell Biol 2003; 23: 4356–4370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lai A, Kennedy BK, Barbie DA, Bertos NR, Yang XJ, Theberge MC et al. RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Mol Cell Biol 2001; 21: 2918–2932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lin D, Ippolito GC, Zong RT, Bryant J, Koslovsky J, Tucker P . Bright/ARID3A contributes to chromatin accessibility of the immunoglobulin heavy chain enhancer. Mol Cancer 2007; 6: 23.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Herrscher RF, Kaplan MH, Lelsz DL, Das C, Scheuermann R, Tucker PW . The immunoglobulin heavy-chain matrix-associating regions are bound by Bright: a B cell-specific trans-activator that describes a new DNA-binding protein family. Genes Dev 1995; 9: 3067–3082.

    Article  CAS  PubMed  Google Scholar 

  23. Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF . The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations. Cell Immunol 2004; 228: 42–53.

    Article  CAS  PubMed  Google Scholar 

  24. Webb CF, Smith EA, Medina KL, Buchanan KL, Smithson G, Dou S . Expression of bright at two distinct stages of B lymphocyte development. J Immunol 1998; 160: 4747–4754.

    CAS  PubMed  Google Scholar 

  25. Oldham AL, Miner CA, Wang HC, Webb CF . The transcription factor Bright plays a role in marginal zone B lymphocyte development and autoantibody production. Mol Immunol 2011; 49: 367–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cariappa A, Tang M, Parng C, Nebelitskiy E, Carroll M, Georgopoulos K et al. The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 2001; 14: 603–615.

    Article  CAS  PubMed  Google Scholar 

  27. Nie Y, Waite J, Brewer F, Sunshine MJ, Littman DR, Zou YR . The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. J Exp Med 2004; 200: 1145–1156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pasqualetto V, Vasseur F, Zavala F, Schneider E, Ezine S . Fas receptor signaling is requisite for B cell differentiation. J Leukoc Biol 2005; 78: 1106–1117.

    Article  CAS  PubMed  Google Scholar 

  29. Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G et al. Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci 2009; 100: 920–926.

    Article  CAS  PubMed  Google Scholar 

  30. Varettoni M, Arcaini L, Zibellini S, Boveri E, Rattotti S, Riboni R et al. Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms. Blood 2013; 121: 2522–2528.

    Article  CAS  PubMed  Google Scholar 

  31. Ruiz-Ballesteros E, Mollejo M, Rodriguez A, Camacho FI, Algara P, Martinez N et al. Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis. Blood 2005; 106: 1831–1838.

    Article  CAS  PubMed  Google Scholar 

  32. Bourachot B, Yaniv M, Muchardt C . Growth inhibition by the mammalian SWI-SNF subunit Brm is regulated by acetylation. EMBO J 2003; 22: 6505–6515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamamichi N, Yamamichi-Nishina M, Mizutani T, Watanabe H, Minoguchi S, Kobayashi N et al. The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential. Oncogene 2005; 24: 5471–5481.

    Article  CAS  PubMed  Google Scholar 

  34. Nagarajan P, Onami TM, Rajagopalan S, Kania S, Donnell R, Venkatachalam S . Role of chromodomain helicase DNA-binding protein 2 in DNA damage response signaling and tumorigenesis. Oncogene 2009; 28: 1053–1062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang WC, Ju TK, Hung MC, Chen CC . Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell 2007; 26: 75–87.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 2013; 121: 1604–1611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Love C, Sun Z, Jima D, Li G, Zhang J, Miles R et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet 2012; 44: 1321–1325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011; 476: 298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 2011; 471: 235–239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Grossmann V, Tiacci E, Holmes AB, Kohlmann A, Martelli MP, Kern W et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011; 118: 6153–6163.

    Article  CAS  PubMed  Google Scholar 

  41. Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Prive GG . Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell 2008; 29: 384–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Capparuccia L, Tamagnone L . Semaphorin signaling in cancer cells and in cells of the tumor microenvironment–two sides of a coin. J Cell Sci 2009; 122 (Pt 11): 1723–1736.

    Article  CAS  PubMed  Google Scholar 

  43. Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S et al. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest 2010; 120: 2684–2698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hou R, Liu L, Anees S, Hiroyasu S, Sibinga NE . The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals. J Cell Biol 2006; 173: 417–429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Skouloudaki K, Puetz M, Simons M, Courbard JR, Boehlke C, Hartleben B et al. Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci USA 2009; 106: 8579–8584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan S et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 2013; 2745: 253–261.

    Article  Google Scholar 

  47. Han S, Witt RM, Santos TM, Polizzano C, Sabatini BL, Ramesh V . Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling. Cell Signal 2008; 20: 1084–1091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Holland S, Coste O, Zhang DD, Pierre SC, Geisslinger G, Scholich K . The ubiquitin ligase MYCBP2 regulates transient receptor potential vanilloid receptor 1 (TRPV1) internalization through inhibition of p38 MAPK signaling. J Biol Chem 2011; 286: 3671–3680.

    Article  CAS  PubMed  Google Scholar 

  49. Pui CH . T cell acute lymphoblastic leukemia: NOTCHing the way toward a better treatment outcome. Cancer Cell 2009; 15: 85–87.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Biobank of HUMV–IFIMAV (Santander, Spain) and the biobank of Hospital de León (BEOCyL) for providing biological samples. This study was supported by grants from the Ministerio de Sanidad y Consumo (RTICC RD06/0020/0107, RD12/0036/0060, PI 12/1682), the Ministerio de Ciencia e Innovación (SAF2008–03871), the Asociación Española Contra el Cáncer (AECC), Spain, and the Nelia et Amadeo Barletta Foundation (Lausanne, Switzerland).

Author information

Authors and Affiliations

  1. Cancer Genomics, IFIMAV Instituto de Formación e Investigación Marqués de Valdecilla, Santander, Spain

    N Martínez, C Almaraz, J P Vaqué & M A Piris

  2. IBBTEC, UC-CSIC-SODERCAN, Instituto de Biomedicina y Biotecnología de Cantabria, Santander, Spain

    I Varela

  3. CNAG Centro Nacional de Análisis Genómico, Barcelona, Spain

    S Derdak, S Beltran, L Agueda, M Gut, J Blanc, M Bayes & I Gut

  4. Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain

    M Mollejo, Y Campos-Martin & L F Casado

  5. Lymphoma and Genomics Research Program, IOR Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    A Rinaldi, I Kwee & F Bertoni

  6. Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland

    I Kwee

  7. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

    I Kwee

  8. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    D Oscier

  9. Department of Cancer Genomics, University of Southampton, Southampton, UK

    J C Strefford

  10. Department of Haematology, Hospital Universitario Doce de Octubre, Madrid, Spain

    J Martinez-Lopez

  11. Department of Haematology, Hospital del Mar, Barcelona, Spain

    A Salar

  12. Department of Cytogenetics, Hospital del Mar and Institut Josep Carreras (IJC), Barcelona, Spain

    F Sole

  13. Dermatology Service, Hospital Universitario Doce de Octubre, Madrid, Spain

    J L Rodriguez-Peralto

  14. Department of Pathology, Hospital de León, León, Spain

    C Diez-Tascón

  15. Department of Pathology, MD Anderson Cancer Center Madrid, Madrid, Spain

    J F García

  16. Department of Pathology, Hospital Clínico Universitario de Santiago, Spain

    M Fraga

  17. Department of Haematology, Hospital Clínico de Salamanca, Salamanca, Spain

    E Sebastián

  18. Department of Pathology, Hospital Universitario La Paz, Madrid, Spain

    J Alvés

  19. Department of Pathology, HGUGM, Madrid, Spain

    J Menárguez

  20. Department of Pathology, Hospital Xeral Cíes, Vigo, Spain

    J González-Carreró

  21. Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    F Bertoni

  22. Department of Pathology, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    M A Piris

Authors
  1. N Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Almaraz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J P Vaqué
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Varela
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Derdak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Beltran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Mollejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Campos-Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Agueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Rinaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. I Kwee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Gut
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Blanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. D Oscier
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J C Strefford
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J Martinez-Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A Salar
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. F Sole
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. J L Rodriguez-Peralto
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. C Diez-Tascón
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. J F García
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. M Fraga
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. E Sebastián
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. J Alvés
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. J Menárguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. J González-Carreró
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. L F Casado
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. M Bayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. F Bertoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. I Gut
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. M A Piris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Piris.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martínez, N., Almaraz, C., Vaqué, J. et al. Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation. Leukemia 28, 1334–1340 (2014). https://doi.org/10.1038/leu.2013.365

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.365

Keywords

This article is cited by

Search

Advanced search

Quick links