Clinical and Translational Oncology

, Volume 15, Issue 1, pp 3–8 | Cite as

Next-generation sequencing reveals the secrets of the chronic lymphocytic leukemia genome

  • Andrew J. Ramsay
  • Alejandra Martínez-Trillos
  • Pedro Jares
  • David Rodríguez
  • Agnieszka Kwarciak
  • Víctor Quesada
Educational Series – Blue Series ADVANCES IN TRANSLATIONAL ONCOLOGY

Abstract

The study of the detailed molecular history of cancer development is one of the most promising techniques to understand and fight this diverse and prevalent disease. Unfortunately, this history is as diverse as cancer itself. Therefore, even with next-generation sequencing techniques, it is not easy to distinguish significant (driver) from random (passenger) events. The International Cancer Genome Consortium (ICGC) was formed to solve this fundamental issue by coordinating the sequencing of samples from 50 different cancer types and/or sub-types that are of clinical and societal importance. The contribution of Spain in this consortium has been focused on chronic lymphocytic leukemia (CLL). This approach has unveiled new and unexpected events in the development of CLL. In this review, we introduce the approaches utilized by the consortium for the study of the CLL genome and discuss the recent results and future perspectives of this work.

Keywords

Chronic lymphocytic leukemia Cancer genome Next-generation sequencing 

References

  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 5:646–674CrossRefGoogle Scholar
  2. 2.
    Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 7239:719–724CrossRefGoogle Scholar
  3. 3.
    Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 7132:153–158CrossRefGoogle Scholar
  4. 4.
    Bozic I, Antal T, Ohtsuki H et al (2010) Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci USA 43:18545–18550CrossRefGoogle Scholar
  5. 5.
    Hudson TJ, Anderson W, Artez A et al (2010) International network of cancer genome projects. Nature 7291:993–998CrossRefGoogle Scholar
  6. 6.
    Zhao J, Grant SF (2011) Advances in whole genome sequencing technology. Curr Pharm Biotechnol 2:293–305CrossRefGoogle Scholar
  7. 7.
    Meyerson M, Gabriel S, Getz G (2010) Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 10:685–696CrossRefGoogle Scholar
  8. 8.
    Ley TJ, Mardis ER, Ding L et al (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 7218:66–72CrossRefGoogle Scholar
  9. 9.
    Campbell PJ, Stephens PJ, Pleasance ED et al (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 6:722–729CrossRefGoogle Scholar
  10. 10.
    Chapman MA, Lawrence MS, Keats JJ et al (2011) Initial genome sequencing and analysis of multiple myeloma. Nature 7339:467–472CrossRefGoogle Scholar
  11. 11.
    Stephens PJ, McBride DJ, Lin ML et al (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 7276:1005–1010CrossRefGoogle Scholar
  12. 12.
    Pleasance ED, Cheetham RK, Stephens PJ et al (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 7278:191–196CrossRefGoogle Scholar
  13. 13.
    Campbell PJ, Yachida S, Mudie LJ et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 7319:1109–1113CrossRefGoogle Scholar
  14. 14.
    Totoki Y, Tatsuno K, Yamamoto S et al (2011) High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet 5:464–469CrossRefGoogle Scholar
  15. 15.
    Parsons DW, Li M, Zhang X et al (2011) The genetic landscape of the childhood cancer medulloblastoma. Science 6016:435–439CrossRefGoogle Scholar
  16. 16.
    Berger MF, Lawrence MS, Demichelis F et al (2011) The genomic complexity of primary human prostate cancer. Nature 7333:214–220CrossRefGoogle Scholar
  17. 17.
    Welch JS, Westervelt P, Ding L et al (2011) Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA 15:1577–1584CrossRefGoogle Scholar
  18. 18.
    Wu G, Broniscer A, McEachron TA et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 3:251–253CrossRefGoogle Scholar
  19. 19.
    Network CGAR (2011) Integrated genomic analyses of ovarian carcinoma. Nature 7353:609–615Google Scholar
  20. 20.
    Puente XS, Pinyol M, Quesada V et al (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 7354:101–105CrossRefGoogle Scholar
  21. 21.
    Quesada V, Conde L, Villamor N et al (2012) Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 1:47–52Google Scholar
  22. 22.
    Wang L, Lawrence MS, Wan Y et al (2011) SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 26:2497–2506CrossRefGoogle Scholar
  23. 23.
    Fabbri G, Rasi S, Rossi D et al (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 7:1389–1401CrossRefGoogle Scholar
  24. 24.
    Rozman C, Montserrat E (1995) Chronic lymphocytic leukemia. N Engl J Med 16:1052–1057CrossRefGoogle Scholar
  25. 25.
    Zenz T, Mertens D, Kuppers R et al (2010) From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 1:37–50Google Scholar
  26. 26.
    Hamblin TJ, Davis Z, Gardiner A et al (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 6:1848–1854Google Scholar
  27. 27.
    Kan Z, Jaiswal BS, Stinson J et al (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 7308:869–873CrossRefGoogle Scholar
  28. 28.
    Grabher C, von Boehmer H, Look AT (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 5:347–359CrossRefGoogle Scholar
  29. 29.
    Weng AP, Ferrando AA, Lee W et al (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 5694:269–271CrossRefGoogle Scholar
  30. 30.
    Palomero T, Lim WK, Odom DT et al (2006) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 48:18261–18266CrossRefGoogle Scholar
  31. 31.
    Tsimberidou AM, Keating MJ (2006) Richter’s transformation in chronic lymphocytic leukemia. Semin Oncol 2:250–256CrossRefGoogle Scholar
  32. 32.
    Kanai M, Hanashiro K, Kim SH et al (2007) Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nat Cell Biol 10:1175–1183CrossRefGoogle Scholar
  33. 33.
    Wang W, Budhu A, Forgues M et al (2005) Temporal and spatial control of nucleophosmin by the Ran–Crm1 complex in centrosome duplication. Nat Cell Biol 8:823–830CrossRefGoogle Scholar
  34. 34.
    Ranganathan P, Yu X, Na C et al (2012) Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood. doi:10.1182/blood-2012-04-423160 Google Scholar
  35. 35.
    O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 5:353–364CrossRefGoogle Scholar
  36. 36.
    Ngo VN, Young RM, Schmitz R et al (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 7332:115–119CrossRefGoogle Scholar
  37. 37.
    Kroll J, Shi X, Caprioli A et al (2005) The BTB-kelch protein KLHL6 is involved in B-lymphocyte antigen receptor signaling and germinal center formation. Mol Cell Biol 19:8531–8540CrossRefGoogle Scholar
  38. 38.
    Dohner H, Stilgenbauer S, Benner A et al (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 26:1910–1916CrossRefGoogle Scholar
  39. 39.
    Klein U, Lia M, Crespo M et al (2010) The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 1:28–40CrossRefGoogle Scholar
  40. 40.
    Calin GA, Dumitru CD, Shimizu M et al (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 24:15524–15529CrossRefGoogle Scholar
  41. 41.
    Golas MM, Sander B, Will CL et al (2003) Molecular architecture of the multiprotein splicing factor SF3b. Science 5621:980–984CrossRefGoogle Scholar
  42. 42.
    Wu L, Multani AS, He H et al (2006) Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 1:49–62CrossRefGoogle Scholar
  43. 43.
    Hockemeyer D, Daniels JP, Takai H et al (2006) Recent expansion of the telomeric complex in rodents: two distinct POT1 proteins protect mouse telomeres. Cell 1:63–77CrossRefGoogle Scholar
  44. 44.
    Nagarajan P, Onami TM, Rajagopalan S et al (2009) Role of chromodomain helicase DNA-binding protein 2 in DNA damage response signaling and tumorigenesis. Oncogene 8:1053–1062CrossRefGoogle Scholar
  45. 45.
    Prazeres H, Torres J, Rodrigues F et al (2011) Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells. Oncogene 11:1302–1317CrossRefGoogle Scholar
  46. 46.
    Quesada V, Ramsay AJ, Lopez-Otin C (2012) Chronic lymphocytic leukemia with SF3B1 mutation. N Engl J Med 26:2530CrossRefGoogle Scholar
  47. 47.
    Rossi D, Bruscaggin A, Spina V et al (2011) Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 26:6904–6908CrossRefGoogle Scholar
  48. 48.
    Yoshida K, Sanada M, Shiraishi Y et al (2011) Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 7367:64–69CrossRefGoogle Scholar
  49. 49.
    Graubert TA, Shen D, Ding L et al (2012) Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 1:53–57Google Scholar
  50. 50.
    Papaemmanuil E, Cazzola M, Boultwood J et al (2011) Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 15:1384–1395CrossRefGoogle Scholar
  51. 51.
    David CJ, Manley JL (2010) Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 21:2343–2364CrossRefGoogle Scholar
  52. 52.
    Folco EG, Coil KE, Reed R (2011) The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region. Genes Dev 5:440–444CrossRefGoogle Scholar
  53. 53.
    Corrionero A, Minana B, Valcarcel J (2011) Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 5:445–459CrossRefGoogle Scholar
  54. 54.
    Chen AA, Marsit CJ, Christensen BC et al (2009) Genetic variation in the vitamin C transporter, SLC23A2, modifies the risk of HPV16-associated head and neck cancer. Carcinogenesis 6:977–981CrossRefGoogle Scholar
  55. 55.
    Bulwin GC, Heinemann T, Bugge V et al (2006) TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression. J Immunol 10:6833–6841Google Scholar
  56. 56.
    Yu B, Zhou X, Li B et al (2011) FOXP1 expression and its clinicopathologic significance in nodal and extranodal diffuse large B-cell lymphoma. Ann Hematol 6:701–708CrossRefGoogle Scholar
  57. 57.
    Brown PJ, Ashe SL, Leich E et al (2008) Potentially oncogenic B-cell activation-induced smaller isoforms of FOXP1 are highly expressed in the activated B cell-like subtype of DLBCL. Blood 5:2816–2824CrossRefGoogle Scholar
  58. 58.
    Garbelli A, Radi M, Falchi F et al (2011) Targeting the human DEAD-box polypeptide 3 (DDX3) RNA helicase as a novel strategy to inhibit viral replication. Curr Med Chem 20:3015–3027CrossRefGoogle Scholar
  59. 59.
    Yedavalli VS, Neuveut C, Chi YH et al (2004) Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function. Cell 3:381–392CrossRefGoogle Scholar
  60. 60.
    van der Maarel SM, Scholten IH, Huber I et al (1996) Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1. Hum Mol Genet 7:887–897CrossRefGoogle Scholar
  61. 61.
    Xiao S, Nalabolu SR, Aster JC et al (1998) FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome. Nat Genet 1:84–87CrossRefGoogle Scholar
  62. 62.
    Grenard P, Bates MK, Aeschlimann D (2001) Evolution of transglutaminase genes: identification of a transglutaminase gene cluster on human chromosome 15q15. Structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase Z. J Biol Chem 35:33066–33078CrossRefGoogle Scholar
  63. 63.
    Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 6024:1553–1558CrossRefGoogle Scholar
  64. 64.
    Service RF (2006) Gene sequencing. The race for the $1000 genome. Science 5767:1544–1546CrossRefGoogle Scholar
  65. 65.
    Maheswaran S, Sequist LV, Nagrath S et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 4:366–377CrossRefGoogle Scholar
  66. 66.
    Leary RJ, Kinde I, Diehl F et al (2010) Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 20:20ra14Google Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2012

Authors and Affiliations

  • Andrew J. Ramsay
    • 1
  • Alejandra Martínez-Trillos
    • 2
  • Pedro Jares
    • 2
  • David Rodríguez
    • 1
  • Agnieszka Kwarciak
    • 1
  • Víctor Quesada
    • 1
  1. 1.Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, IUOPAUniversidad de OviedoOviedoSpain
  2. 2.Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, IDIBAPSBarcelonaSpain

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