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Recurrent Gene Mutations in CLL

  • Alejandra Martínez-Trillos
  • Víctor Quesada
  • Neus Villamor
  • Xose S. Puente
  • Carlos López-Otín
  • Elías CampoEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 792)

Abstract

Next-generation sequencing of whole genomes and exomes in chronic lymphocytic leukemia (CLL) has provided the first comprehensive view of somatic mutations in this disease. Subsequent studies have characterized the oncogenic pathways and clinical implications of a number of these mutations. The global number of somatic mutations per case is lower than those described in solid tumors but is in agreement with previous estimates of less than one mutation per megabase in hematological neoplasms. The number and pattern of somatic mutations differ in tumors with unmutated and mutated IGHV, extending at the genomic level the clinical differences observed in these two CLL subtypes. One of the striking conclusions of these studies has been the marked genetic heterogeneity of the disease, with a relatively large number of genes recurrently mutated at low frequency and only a few genes mutated in up to 10–15 % of the patients. The mutated genes tend to cluster in different pathways that include NOTCH1 signaling, RNA splicing and processing machinery, innate inflammatory response, Wnt signaling, and DNA damage and cell cycle control, among others. These results highlight the molecular heterogeneity of CLL and may provide new biomarkers and potential therapeutic targets for the diagnosis and management of the disease.

Keywords

Chronic lymphocytic leukemia Next-generation sequencing Somatic mutations NOTCH1 SF3B1 MYD88 

Notes

Acknowledgements

The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII. We are grateful to the members of our groups for their contribution to the studies of the consortium and N. Villahoz and M.C. Muro for their excellent work in the coordination of the CLL Spanish Consortium.

References

  1. 1.
    Zenz T, Mertens D, Kuppers R, et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010;10:37–50.PubMedGoogle Scholar
  2. 2.
    Gaidano G, Foa R, Dalla-Favera R. Molecular pathogenesis of chronic lymphocytic leukemia. J Clin Invest. 2012;122:3432–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Tsimberidou AM, Keating MJ. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer. 2005;103:216–28.PubMedCrossRefGoogle Scholar
  4. 4.
    Kulis M, Heath S, Bibikova M, et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat Genet. 2012;44:1236–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet. 2010;11:685–96.PubMedCrossRefGoogle Scholar
  6. 6.
    International Cancer Genome Consortium, Hudson TJ, Anderson W, et al. International network of cancer genome projects. Nature. 2010;464:993–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389–401.PubMedCrossRefGoogle Scholar
  9. 9.
    Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2012;44:47–52.CrossRefGoogle Scholar
  10. 10.
    Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365:2497–506.PubMedCrossRefGoogle Scholar
  11. 11.
    Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood. 2012;119:192–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.PubMedCrossRefGoogle Scholar
  13. 13.
    Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109:3879–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490:116–20.PubMedCrossRefGoogle Scholar
  16. 16.
    ICGC MMML-Seq Project, Richter J, Schlesner M, et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet. 2012;44:1316–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Love C, Sun Z, Jima D, et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012;44:1321–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.PubMedCrossRefGoogle Scholar
  19. 19.
    Nik-Zainal S, Alexandrov LB, Wedge DC, et al. Mutational processes molding the genomes of 21 breast cancers. Cell. 2012;149:979–93.PubMedCrossRefGoogle Scholar
  20. 20.
    Nik-Zainal S, Van Loo P, Wedge DC, et al. The life history of 21 breast cancers. Cell. 2012;149:994–1007.PubMedCrossRefGoogle Scholar
  21. 21.
    Pleasance ED, Stephens PJ, O’Meara S, et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010;463:184–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Schuster-Bockler B, Lehner B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature. 2012;488:504–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Tadmor T, Tiacci E, Falini B, Polliack A. The BRAF-V600E mutation in hematological malignancies: a new player in hairy cell leukemia and Langerhans cell histiocytosis. Leuk Lymphoma. 2012;53:2339–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367:826–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Allman D, Punt JA, Izon DJ, et al. An invitation to T and more: notch signaling in lymphopoiesis. Cell. 2002;109(Suppl):S1–11.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematology Am Soc Hematol Educ Program. 2009;353–61.Google Scholar
  28. 28.
    Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269–71.PubMedCrossRefGoogle Scholar
  29. 29.
    De Keersmaecker K, Michaux L, Bosly A, et al. Rearrangement of NOTCH1 or BCL3 can independently trigger progression of CLL. Blood. 2012;119:3864–6.PubMedCrossRefGoogle Scholar
  30. 30.
    O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.PubMedCrossRefGoogle Scholar
  31. 31.
    Rosati E, Sabatini R, Rampino G, et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. 2009;113:856–65.PubMedCrossRefGoogle Scholar
  32. 32.
    Mansouri L, Cahill N, Gunnarsson R, et al. NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia. 2012;27(2):512–4.PubMedGoogle Scholar
  33. 33.
    Zainuddin N, Murray F, Kanduri M, et al. TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia. Leuk Res. 2011;35:272–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood. 2012;119:329–31.PubMedCrossRefGoogle Scholar
  35. 35.
    Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119:521–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Oscier DG, Rose-Zerilli MJ, Winkelmann N, et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood. 2012;121(3):468–75.PubMedCrossRefGoogle Scholar
  37. 37.
    Villamor N, Conde L, Martinez-trillos A, et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia. 2013;27(5):1100–6. doi: 10.1038/leu.2012.357.PubMedCrossRefGoogle Scholar
  38. 38.
    Lopez C, Delgado J, Costa D, et al. Different distribution of NOTCH1 mutations in chronic lymphocytic leukemia with isolated trisomy 12 or associated with other chromosomal alterations. Genes Chromosomes Cancer. 2012;51:881–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012;158:426–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Shedden K, Li Y, Ouillette P, Malek SN. Characteristics of chronic lymphocytic leukemia with somatically acquired mutations in NOTCH1 exon 34. Leukemia. 2012;26:1108–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Rasi S, Monti S, Spina V, et al. Analysis of NOTCH1 mutations in monoclonal B-cell lymphocytosis. Haematologica. 2012;97:153–4.PubMedCrossRefGoogle Scholar
  42. 42.
    Orlandi EM, Rossi M. NOTCH1 mutations in chronic lymphocytic leukemia with trisomy 12. Genes Chromosomes Cancer. 2012;51:1063–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Schuh A, Becq J, Humphray S, et al. Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns. Blood. 2012;120:4191–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119:1963–71.PubMedCrossRefGoogle Scholar
  45. 45.
    Kiel MJ, Velusamy T, Betz BL, et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med. 2012;209:1553–65.PubMedCrossRefGoogle Scholar
  46. 46.
    Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012;209:1537–51.PubMedCrossRefGoogle Scholar
  47. 47.
    Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Papaemmanuil E, Cazzola M, Boultwood J, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95.PubMedCrossRefGoogle Scholar
  49. 49.
    Visconte V, Makishima H, Jankowska A, et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia. 2012;26:542–5.PubMedCrossRefGoogle Scholar
  50. 50.
    David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 2010;24:2343–64.PubMedCrossRefGoogle Scholar
  51. 51.
    Folco EG, Coil KE, Reed R. The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region. Genes Dev. 2011;25:440–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Corrionero A, Minana B, Valcarcel J. Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev. 2011;25:445–59.PubMedCrossRefGoogle Scholar
  53. 53.
    Brown PJ, Ashe SL, Leich E, et al. Potentially oncogenic B-cell activation-induced smaller isoforms of FOXP1 are highly expressed in the activated B cell-like subtype of DLBCL. Blood. 2008;111:2816–24.PubMedCrossRefGoogle Scholar
  54. 54.
    Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood. 2011;118:6904–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Ramsay AJ, Rodriguez D, Villamor N, et al. Frequent somatic mutations in components of the RNA processing machinery in chronic lymphocytic leukemia. Leukemia. 2012.Google Scholar
  56. 56.
    Quiroga MP, Balakrishnan K, Kurtova AV, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood. 2009;114:1029–37.PubMedCrossRefGoogle Scholar
  57. 57.
    Schulz A, Toedt G, Zenz T, et al. Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2. Haematologica. 2011;96:408–16.PubMedCrossRefGoogle Scholar
  58. 58.
    Burger JA, Quiroga MP, Hartmann E, et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood. 2009;113:3050–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Zenz T, Mertens D, Stilgenbauer S. Biological diversity and risk-adapted treatment of chronic lymphocytic leukemia. Haematologica. 2010;95:1441–3.PubMedCrossRefGoogle Scholar
  60. 60.
    Rossi D, Fangazio M, Rasi S, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood. 2012;119:2854–62.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Alejandra Martínez-Trillos
    • 1
  • Víctor Quesada
    • 2
  • Neus Villamor
    • 1
  • Xose S. Puente
    • 2
  • Carlos López-Otín
    • 2
  • Elías Campo
    • 3
    Email author
  1. 1.Unidad de Hematopatologia, Departamento de Anatomía Patológica, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS)Universitat de BarcelonaBarcelonaSpain
  2. 2.Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología-IUOPAUniversidad de OviedoOviedoSpain
  3. 3.Hematopathology Unit, Hospital ClinicUniversity of BarcelonaBarcelonaSpain

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