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Myeloma

Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms

Leukemia volume 28, pages 384–390 (2014)Cite this article

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Abstract

The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.

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References

  1. Palumbo A, Anderson K . Multiple myeloma. N Engl J Med 2011; 364: 1046–1060.

    Article  CAS  Google Scholar 

  2. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564–569.

    Article  Google Scholar 

  3. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM . A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113: 5418–5422.

    Article  CAS  Google Scholar 

  4. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121: 749–757.

    Article  Google Scholar 

  5. Morgan GJ, Walker BA, Davies FE . The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12: 335–348.

    Article  CAS  Google Scholar 

  6. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002; 100: 1417–1424.

    CAS  Google Scholar 

  7. Chiecchio L, Dagrada GP, Ibrahim AH, Dachs Cabanas E, Protheroe RK, Stockley DM et al. Timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context. Haematologica 2009; 94: 1708–1713.

    Article  CAS  Google Scholar 

  8. Magrangeas F, Lode L, Wuilleme S, Minvielle S, vet-Loiseau H . Genetic heterogeneity in multiple myeloma. Leukemia 2005; 19: 191–194.

    Article  CAS  Google Scholar 

  9. Salhia B, Baker A, Ahmann G, Auclair D, Fonseca R, Carpten J . DNA methylation analysis determines the high frequency of genic hypomethylation and low frequency of hypermethylation events in plasma cell tumors. Cancer Res 2010; 70: 6934–6944.

    Article  CAS  Google Scholar 

  10. Walker BA, Wardell CP, Chiecchio L, Smith EM, Boyd KD, Neri A et al. Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. Blood 2011; 117: 553–562.

    Article  CAS  Google Scholar 

  11. Dib A, Gabrea A, Glebov OK, Bergsagel PL, Kuehl WM . Characterization of MYC translocations in multiple myeloma cell lines. Journal of the National Cancer Institute. Monographs 2008; 39: 25–31.

    Article  CAS  Google Scholar 

  12. Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O'Connor SM et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003; 102: 4504–4511.

    Article  CAS  Google Scholar 

  13. Kaiser MF, Walker BA, Hockley SL, Begum DB, Wardell CP, Gonzalez D et al. A TC classification based predictor for multiple myeloma using multiplexed real-time quantitative PCR. Leukemia 2013; 27: 1754–1757.

    Article  CAS  Google Scholar 

  14. Lopez-Corral L, Gutierrez NC, Vidriales MB, Mateos MV, Rasillo A, Garcia-Sanz R et al. The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res 2011; 17: 1692–1700.

    Article  CAS  Google Scholar 

  15. Lopez-Corral L, Mateos MV, Corchete LA, Sarasquete ME, de la Rubia J, de Arriba F et al. Genomic analysis of high-risk smoldering multiple myeloma. Haematologica 2012; 97: 1439–1443.

    Article  Google Scholar 

  16. Lopez-Corral L, Sarasquete ME, Bea S, Garcia-Sanz R, Mateos MV, Corchete LA et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia 2012; 26: 2521–2529.

    Article  CAS  Google Scholar 

  17. Chiecchio L, Dagrada GP, Protheroe RK, Stockley DM, Smith AG, Orchard KH et al. Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. Haematologica 2009; 94: 1024–1028.

    Article  CAS  Google Scholar 

  18. Weston-Bell N, Gibson J, John M, Ennis S, Pfeifer S, Cezard T et al. Exome sequencing in tracking clonal evolution in multiple myeloma following therapy. Leukemia 2013; 27: 1188–1191.

    Article  CAS  Google Scholar 

  19. Swanton C . Intratumor heterogeneity: Evolution through space and time. Cancer Res 2012; 72: 4875–4882.

    Article  CAS  Google Scholar 

  20. Greaves M, Maley CC . Clonal evolution in cancer. Nature 2012; 481: 306–313.

    Article  CAS  Google Scholar 

  21. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl JMed 2012; 366: 883–892.

    Article  CAS  Google Scholar 

  22. Nik-Zainal S, Van Loo P, Wedge David C, Alexandrov Ludmil B, Greenman Christopher D, Lau King W et al. The life history of 21 breast cancers. Cell 2012; 149: 994–1007.

    Article  CAS  Google Scholar 

  23. Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011; 469: 356–361.

    Article  CAS  Google Scholar 

  24. Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356: 2582–2590.

    Article  CAS  Google Scholar 

  25. Perez-Persona E, Vidriales MB, Mateo G, Garcia-Sanz R, Mateos MV, de Coca AG et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007; 110: 2586–2592.

    Article  CAS  Google Scholar 

  26. Gutierrez NC, Castellanos MV, Martin ML, Mateos MV, Hernandez JM, Fernandez M et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 2007; 21: 143–150.

    Article  CAS  Google Scholar 

  27. Walker BA, Wardell CP, Melchor L, Hulkki S, Potter NE, Johnson DC et al. Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood 2012; 120: 1077–1086.

    Article  CAS  Google Scholar 

  28. Lunter G, Goodson M . Stampy: A statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res 2011; 21: 936–939.

    Article  CAS  Google Scholar 

  29. Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25: 1754–1760.

    Article  CAS  Google Scholar 

  30. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al. The Genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297–1303.

    Article  CAS  Google Scholar 

  31. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456: 66–72.

    Article  CAS  Google Scholar 

  32. Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 2010; 465: 473–477.

    Article  CAS  Google Scholar 

  33. Colla S, Morandi F, Lazzaretti M, Rizzato R, Lunghi P, Bonomini S et al. Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. Leukemia 2005; 19: 2166–2176.

    Article  CAS  Google Scholar 

  34. Giuliani N, Colla S, Morandi F, Lazzaretti M, Sala R, Bonomini S et al. Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood 2005; 106: 2472–2483.

    Article  CAS  Google Scholar 

  35. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al. COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 2011; 39 (Database issue): D945–D950.

    Article  CAS  Google Scholar 

  36. Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S . Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 2011; 118: 675–678.

    Article  CAS  Google Scholar 

  37. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27–40.

    Article  CAS  Google Scholar 

  38. Liu P, Lu Y, Liu H, Wen W, Jia D, Wang Y et al. Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice. Mol Cancer Res 2012; 10: 66–74.

    Article  CAS  Google Scholar 

  39. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA 2012; 109: 3879–3884.

    Article  CAS  Google Scholar 

  40. Wang H, Ozaki T, Shamim Hossain M, Nakamura Y, Kamijo T, Xue X et al. A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53. Biochem Biophys Res Commun 2008; 370: 594–598.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the Institute of Cancer Research Tumour Profiling Unit for their support and technical expertise in this study. This study was supported by grants from the Myeloma UK, Cancer Research UK and the National Institutes of Health Biomedical Research Centre at the Royal Marsden Hospital.

Author information

Author notes

  1. B A Walker and C P Wardell: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Pathology, Molecular Haematology, Haemato-Oncology Research Unit, The Institute of Cancer Research, London, UK

    B A Walker, C P Wardell, L Melchor, A Brioli, D C Johnson, M F Kaiser, F Mirabella, D Gonzalez & G J Morgan

  2. Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy

    A Brioli

  3. Department of Hematology, University Hospital of Salamanca, Centro de Investigacion del Cancer (CIC) de Salamanca, Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain

    L Lopez-Corral, N C Gutiérrez, R Garcia-Sanz & J San Miguel

  4. Illumina Cambridge Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, UK

    S Humphray, L Murray, M Ross & D Bentley

  5. Division of Molecular Pathology, Targeted Myeloma Treatment, Haemato-Oncology Research Unit, The Institute of Cancer Research, London, UK

    F E Davies

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Correspondence to G J Morgan.

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Competing interests

SH, LM, MR and DB are employed by Illumina Cambridge Ltd. The remaining authors declare no conflict of interest.

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Walker, B., Wardell, C., Melchor, L. et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28, 384–390 (2014). https://doi.org/10.1038/leu.2013.199

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