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Genomic Aberrations in Multiple Myeloma

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Plasma Cell Dyscrasias

Part of the book series: Cancer Treatment and Research ((CTAR,volume 169))

Abstract

Multiple myeloma (MM) is a genetically complex disease. The past few years have seen an evolution in cancer research with the emergence of next-generation sequencing (NGS), enabling high throughput sequencing of tumors—including whole exome, whole genome, RNA, and single-cell sequencing as well as genome-wide association study (GWAS). A few inherited variants have been described, counting for some cases of familial disease. Hierarchically, primary events in MM can be divided into hyperdiploid (HDR) and nonhyperdiploid subtypes. HRD tumors are characterized by trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and/or 21. Non-HRD tumors harbor IGH translocations, mainly t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). Secondary events participate to the tumor progression and consist in secondary translocation involving MYC, copy number variations (CNV) and somatic mutations (such as mutations in KRAS, NRAS, BRAF, P53). Moreover, the dissection of clonal heterogeneity helps to understand the evolution of the disease. The following review provides a comprehensive review of the genomic landscape in MM.

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References

  1. Altieri A, Chen B, Bermejo JL, Castro F, Hemminki K (2006) Familial risks and temporal incidence trends of multiple myeloma. Eur J Cancer 42(11):1661–1670

    Article  PubMed  Google Scholar 

  2. Broderick P, Chubb D, Johnson DC et al (2012) Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet 44(1):58–61

    Article  CAS  Google Scholar 

  3. Chubb D, Weinhold N, Broderick P et al (2013) Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet 45(10):1221–1225

    Article  CAS  PubMed  Google Scholar 

  4. Weinhold N, Johnson DC, Chubb D et al (2013) The CCND1 c.870G > A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nat Genet 45(5):522–525

    Article  CAS  PubMed  Google Scholar 

  5. Landgren O, Graubard BI, Katzmann JA et al (2014) Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the national health and nutritional examination survey. Leukemia 28(7):1537–1542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr (2005) Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106(1):296–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS, Kuehl WM (1996) Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88(2):674–681

    CAS  PubMed  Google Scholar 

  8. Shaughnessy J Jr, Gabrea A, Qi Y et al (2001) Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 98(1):217–223

    Article  CAS  PubMed  Google Scholar 

  9. Hurt EM, Wiestner A, Rosenwald A et al (2004) Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 5(2):191–199

    Article  CAS  PubMed  Google Scholar 

  10. Prideaux SM, Conway O’Brien E, Chevassut TJ (2014) The genetic architecture of multiple myeloma. Adv Hematol 2014:864058

    Google Scholar 

  11. Zhan F, Huang Y, Colla S et al (2006) The molecular classification of multiple myeloma. Blood 108(6):2020–2028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Keats JJ, Reiman T, Maxwell CA et al (2003) In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101(4):1520–1529

    Article  CAS  PubMed  Google Scholar 

  13. Fonseca R, Blood E, Rue M et al (2003) Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101(11):4569–4575

    Article  CAS  PubMed  Google Scholar 

  14. Chang H, Sloan S, Li D et al (2004) The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 125(1):64–68

    Article  PubMed  Google Scholar 

  15. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL (1998) The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92(9):3025–3034

    CAS  PubMed  Google Scholar 

  16. Walker BA, Wardell CP, Johnson DC et al (2013) Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood 121(17):3413–3419

    Article  CAS  PubMed  Google Scholar 

  17. Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy J Jr (2003) A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101(6):2374–2376

    Article  CAS  PubMed  Google Scholar 

  18. Keats JJ, Maxwell CA, Taylor BJ et al (2005) Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 105(10):4060–4069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martinez-Garcia E, Popovic R, Min DJ et al (2011) The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 117(1):211–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pei H, Zhang L, Luo K et al (2011) MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470(7332):124–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hebraud B, Magrangeas F, Cleynen A et al (2015) Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience. Blood 125(13):2095–2100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917

    Article  CAS  PubMed  Google Scholar 

  23. Avet-Loiseau H, Leleu X, Roussel M et al (2010) Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 28(30):4630–4634

    Article  CAS  PubMed  Google Scholar 

  24. Avet-Loiseau H, Attal M, Moreau P et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109(8):3489–3495

    Article  CAS  PubMed  Google Scholar 

  25. Walker BA, Wardell CP, Murison A et al (2015) APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat commun 6:6997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hanamura I, Iida S, Akano Y et al (2001) Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations. Jpn J Cancer Res Gann 92(6):638–644

    Article  CAS  PubMed  Google Scholar 

  27. Ross FM, Ibrahim AH, Vilain-Holmes A et al (2005) Age has a profound effect on the incidence and significance of chromosome abnormalities in myeloma. Leukemia 19(9):1634–1642

    Article  CAS  PubMed  Google Scholar 

  28. Ross FM, Chiecchio L, Dagrada G et al (2010) The t(14;20) is a poor prognostic factor in myeloma but is associated with long-term stable disease in monoclonal gammopathies of undetermined significance. Haematologica 95(7):1221–1225

    Article  PubMed  PubMed Central  Google Scholar 

  29. Smadja NV, Fruchart C, Isnard F et al (1998) Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia 12(6):960–969

    Article  CAS  PubMed  Google Scholar 

  30. Onodera N, McCabe NR, Rubin CM (1992) Formation of a hyperdiploid karyotype in childhood acute lymphoblastic leukemia. Blood 80(1):203–208

    CAS  PubMed  Google Scholar 

  31. Fonseca R, Debes-Marun CS, Picken EB et al (2003) The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 102(7):2562–2567

    Article  CAS  PubMed  Google Scholar 

  32. Pawlyn C, Melchor L, Murison A et al (2015) Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood 125(5):831–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chng WJ, Kumar S, Vanwier S et al (2007) Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 67(7):2982–2989

    Article  CAS  PubMed  Google Scholar 

  34. Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C (2001) Groupe Francais de Cytogenetique H. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood 98(7):2229–2238

    Article  CAS  PubMed  Google Scholar 

  35. Carrasco DR, Tonon G, Huang Y et al (2006) High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9(4):313–325

    Article  CAS  PubMed  Google Scholar 

  36. Walker BA, Leone PE, Chiecchio L et al (2010) A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood 116(15):e56–65

    Article  CAS  PubMed  Google Scholar 

  37. Walker BA, Leone PE, Jenner MW et al (2006) Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood 108(5):1733–1743

    Article  CAS  PubMed  Google Scholar 

  38. Annunziata CM, Davis RE, Demchenko Y et al (2007) Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12(2):115–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Keats JJ, Fonseca R, Chesi M et al (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12(2):131–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hanamura I, Stewart JP, Huang Y et al (2006) Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 108(5):1724–1732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Boyd KD, Ross FM, Chiecchio L et al (2012) A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia 26(2):349–355

    Article  CAS  PubMed  Google Scholar 

  42. Chang H, Qi X, Jiang A, Xu W, Young T, Reece D (2010) 1p21 deletions are strongly associated with 1q21 gains and are an independent adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma. Bone Marrow Transplant 45(1):117–121

    Article  CAS  PubMed  Google Scholar 

  43. Fonseca R, Bergsagel PL, Drach J et al (2009) International myeloma working group molecular classification of multiple myeloma: spotlight review. Leukemia 23(12):2210–2221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shaughnessy J (2005) Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology 10(Suppl 1):117–126

    Article  CAS  PubMed  Google Scholar 

  45. Shi L, Wang S, Zangari M et al (2010) Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget 1(1):22–33

    Article  PubMed  PubMed Central  Google Scholar 

  46. Boyd KD, Ross FM, Walker BA et al (2011) Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival. Clin Cancer Res Official J Am Assoc Cancer Res 17(24):7776–7784

    Article  CAS  Google Scholar 

  47. Chang H, Jiang A, Qi C, Trieu Y, Chen C, Reece D (2010) Impact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone. Leuk lymphoma 51(11):2084–2091

    Article  CAS  PubMed  Google Scholar 

  48. Chapman MA, Lawrence MS, Keats JJ et al (2011) Initial genome sequencing and analysis of multiple myeloma. Nature 471(7339):467–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Leone PE, Walker BA, Jenner MW et al (2008) Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin Cancer Res Official J Am Assoc Cancer Res 14(19):6033–6041

    Article  CAS  Google Scholar 

  50. Fonseca R, Oken MM, Harrington D et al (2001) Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 15(6):981–986

    Article  CAS  PubMed  Google Scholar 

  51. Avet-Loiseau H, Li JY, Morineau N et al (1999) Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. Blood 94(8):2583–2589

    CAS  PubMed  Google Scholar 

  52. Chiecchio L, Protheroe RK, Ibrahim AH et al (2006) Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia 20(9):1610–1617

    Article  CAS  PubMed  Google Scholar 

  53. Avet-Louseau H, Daviet A, Sauner S, Bataille R (2000) Intergroupe Francophone du M. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 111(4):1116–1117

    Article  CAS  PubMed  Google Scholar 

  54. Tiedemann RE, Gonzalez-Paz N, Kyle RA et al (2008) Genetic aberrations and survival in plasma cell leukemia. Leukemia 22(5):1044–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lode L, Eveillard M, Trichet V et al (2010) Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica 95(11):1973–1976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Drach J, Ackermann J, Fritz E et al (1998) Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 92(3):802–809

    CAS  PubMed  Google Scholar 

  57. Lawrence MS, Stojanov P, Polak P et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dziembowski A, Lorentzen E, Conti E, Seraphin B (2007) A single subunit, Dis3, is essentially responsible for yeast exosome core activity. Nat Struct Mol Biol 14(1):15–22

    Article  CAS  PubMed  Google Scholar 

  59. Schmid M, Jensen TH (2008) The exosome: a multipurpose RNA-decay machine. Trends Biochem Sci 33(10):501–510

    Article  CAS  PubMed  Google Scholar 

  60. Lohr JG, Stojanov P, Carter SL et al (2014) Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 25(1):91–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tam W, Gomez M, Chadburn A, Lee JW, Chan WC, Knowles DM (2006) Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 107(10):4090–4100

    Article  CAS  PubMed  Google Scholar 

  62. Pasqualucci L, Compagno M, Houldsworth J et al (2006) Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med 203(2):311–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bolli N, Avet-Loiseau H, Wedge DC et al (2014) Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 5:2997

    Article  PubMed  PubMed Central  Google Scholar 

  64. Anderson K, Lutz C, van Delft FW et al (2011) Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469(7330):356–361

    Article  CAS  PubMed  Google Scholar 

  65. Bahlis NJ (2012) Darwinian evolution and tiding clones in multiple myeloma. Blood 120(5):927–928

    Article  CAS  PubMed  Google Scholar 

  66. Melchor L, Brioli A, Wardell CP et al (2014) Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma. Leukemia 28(8):1705–1715

    Article  CAS  PubMed  Google Scholar 

  67. Walker BA, Wardell CP, Melchor L et al (2014) Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28(2):384–390

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA

    Salomon Manier, Karma Salem, Siobhan V. Glavey, Aldo M. Roccaro & Irene M. Ghobrial

  2. Department of Hematology, Lille Hospital University, Lille, France

    Salomon Manier

  3. Department of Hematology, CREA Laboratory, ASST-Spedali Civili di Brescia, Brescia, BS, Italy

    Aldo M. Roccaro

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  1. Salomon Manier
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  2. Karma Salem
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  3. Siobhan V. Glavey
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  4. Aldo M. Roccaro
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  5. Irene M. Ghobrial
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Correspondence to Irene M. Ghobrial .

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Editors and Affiliations

  1. Dept. of Medical Oncolgy/Hematology,, ASST-Spedali Civili di Brescia Dept. of Medical Oncolgy/Hematology,, Brescia, Brescia, Italy

    Aldo M. Roccaro

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Irene M. Ghobrial

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Manier, S., Salem, K., Glavey, S.V., Roccaro, A.M., Ghobrial, I.M. (2016). Genomic Aberrations in Multiple Myeloma. In: Roccaro, A., Ghobrial, I. (eds) Plasma Cell Dyscrasias. Cancer Treatment and Research, vol 169. Springer, Cham. https://doi.org/10.1007/978-3-319-40320-5_3

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  • DOI: https://doi.org/10.1007/978-3-319-40320-5_3

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