The Genomics of Multiple Myeloma and Its Relevance in the Molecular Classification and Risk Stratification of the Disease

  • Antonino Neri
  • Luca Agnelli


Multiple myeloma, an incurable disease characterized by uncontrolled proliferation of Ig-secreting plasma cells, is the second most frequent hematologic malignancies. By virtue of its clinical, biological, and molecular heterogeneity, it represents a distinctive challenge for the application of new high-throughput technologies, with the aims of a better comprehension of the molecular basis of the disease, a fine stratification and early identification of high-risk patients, and to gain insights towards targeted therapy. Particularly, over the last decade, global gene and microRNA expression, and genome-wide DNA profilings have been widely used to investigate the genomic alterations underlying the bio-clinical heterogeneity in multiple myeloma. Each approach led to promising results, either per se or when the data have been analyzed in an integrated fashion. Herein, we describe some of the most referenced or peculiar “–omic” approaches that had significantly improved the knowledge of multiple myeloma disease.


Multiple Myeloma miRNA Expression Profile Nonnegative Matrix Factorization Plasma Cell Leukaemia International Staging System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are grateful to Stefania Bortoluzzi for the original design and the provision of Fig. 16.2; and to Marta Lionetti, Luisa Lombardi and Domenica Ronchetti for the critical assessment of the text.


  1. 1.
    Kuehl WM, Bergsagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2(3):175–187. doi: 10.1038/nrc746 PubMedCrossRefGoogle Scholar
  2. 2.
    Kyle RA, Rajkumar SV (2003) Monoclonal gammopathies of undetermined significance: a review. Immunol Rev 194:112–139PubMedCrossRefGoogle Scholar
  3. 3.
    Seidl S, Kaufmann H, Drach J (2003) New insights into the pathophysiology of multiple myeloma. Lancet Oncol 4(9):557–564PubMedCrossRefGoogle Scholar
  4. 4.
    International Myeloma Working Group (2003) Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121(5):749–757CrossRefGoogle Scholar
  5. 5.
    Kyle RA, Rajkumar SV (2009) Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 23(1):3–9. doi: 10.1038/leu.2008.291 PubMedCrossRefGoogle Scholar
  6. 6.
    Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36(3):842–854PubMedCrossRefGoogle Scholar
  7. 7.
    Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J (2005) International staging system for multiple myeloma. J Clin Oncol 23(15):3412–3420. doi: 10.1200/JCO.2005.04.242 PubMedCrossRefGoogle Scholar
  8. 8.
    Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H (2004) Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64(4):1546–1558PubMedCrossRefGoogle Scholar
  9. 9.
    Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364(11):1046–1060. doi: 10.1056/NEJMra1011442 PubMedCrossRefGoogle Scholar
  10. 10.
    Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R, Gertz MA, Greipp PR, Hayman SR, Kyle RA, Lacy MQ, Lust JA, Reeder CB, Roy V, Russell SJ, Short KE, Stewart AK, Witzig TE, Zeldenrust SR, Dalton RJ, Rajkumar SV, Bergsagel PL (2009) Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 84(12):1095–1110. doi: 10.4065/mcp.2009.0603 PubMedCrossRefGoogle Scholar
  11. 11.
    Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109(8):3489–3495. doi: 10.1182/blood-2006-08-040410 PubMedCrossRefGoogle Scholar
  12. 12.
    De Vos J, Thykjaer T, Tarte K, Ensslen M, Raynaud P, Requirand G, Pellet F, Pantesco V, Reme T, Jourdan M, Rossi JF, Orntoft T, Klein B (2002) Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays. Oncogene 21(44):6848–6857. doi: 10.1038/sj.onc.1205868 PubMedCrossRefGoogle Scholar
  13. 13.
    Magrangeas F, Nasser V, Avet-Loiseau H, Loriod B, Decaux O, Granjeaud S, Bertucci F, Birnbaum D, Nguyen C, Harousseau JL, Bataille R, Houlgatte R, Minvielle S (2003) Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood 101(12):4998–5006. doi: 10.1182/blood-2002-11-3385 PubMedCrossRefGoogle Scholar
  14. 14.
    Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349(26):2483–2494. doi: 10.1056/NEJMoa030847 PubMedCrossRefGoogle Scholar
  15. 15.
    Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van Rhee F, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J Jr (2002) Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 99(5):1745–1757PubMedCrossRefGoogle Scholar
  16. 16.
    Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr (2003) Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood 101(3):1128–1140. doi: 10.1182/blood-2002-06-1737 PubMedCrossRefGoogle Scholar
  17. 17.
    Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O’Connor SM, Fenton JA, Hideshima T, Chauhan D, Tai IT, Robinson E, Auclair D, Rees K, Gonzalez D, Ashcroft AJ, Dasgupta R, Mitsiades C, Mitsiades N, Chen LB, Wong WH, Munshi NC, Morgan GJ, Anderson KC (2003) Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 102(13):4504–4511. doi: 10.1182/blood-2003-01- PubMedCrossRefGoogle Scholar
  18. 18.
    Mattioli M, Agnelli L, Fabris S, Baldini L, Morabito F, Bicciato S, Verdelli D, Intini D, Nobili L, Cro L, Pruneri G, Callea V, Stelitano C, Maiolo AT, Lombardi L, Neri A (2005) Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma. Oncogene 24(15):2461–2473. doi: 10.1038/sj.onc.1208447 PubMedCrossRefGoogle Scholar
  19. 19.
    Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC (2004) Advances in biology of multiple myeloma: clinical applications. Blood 104(3):607–618. doi: 10.1182/blood-2004-01-0037 PubMedCrossRefGoogle Scholar
  20. 20.
    Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, Dewald GW, Van Ness B, Van Wier SA, Henderson KJ, Bailey RJ, Greipp PR (2003) Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101(11):4569–4575. doi: 10.1182/blood-2002-10-3017 PubMedCrossRefGoogle Scholar
  21. 21.
    Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, Bataille R, Avet-Loiseau H (2002) Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100(5):1579–1583. doi: 10.1182/blood-2002-03-0749 PubMedCrossRefGoogle Scholar
  22. 22.
    Agnelli L, Bicciato S, Mattioli M, Fabris S, Intini D, Verdelli D, Baldini L, Morabito F, Callea V, Lombardi L, Neri A (2005) Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. J Clin Oncol 23(29):7296–7306. doi: 10.1200/JCO.2005.01.3870 PubMedCrossRefGoogle Scholar
  23. 23.
    Buyse M, Sargent DJ, Grothey A, Matheson A, de Gramont A (2010) Biomarkers and surrogate end points–the challenge of statistical validation. Nat Rev Clin Oncol 7(6):309–317. doi: 10.1038/nrclinonc.2010.43 PubMedCrossRefGoogle Scholar
  24. 24.
    Barlogie B, Tricot G, Rasmussen E, Anaissie E, van Rhee F, Zangari M, Fassas A, Hollmig K, Pineda-Roman M, Shaughnessy J, Epstein J, Crowley J (2006) Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107(7):2633–2638. doi: 10.1182/blood-2005-10-4084 PubMedCrossRefGoogle Scholar
  25. 25.
    Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B (2008) Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol 140(6):625–634. doi: 10.1111/j.1365-2141.2007.06921.x PubMedCrossRefGoogle Scholar
  26. 26.
    Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, Epstein J, Yaccoby S, Sawyer J, Burington B, Anaissie E, Hollmig K, Pineda-Roman M, Tricot G, van Rhee F, Walker R, Zangari M, Crowley J, Barlogie B, Shaughnessy JD Jr (2006) The molecular classification of multiple myeloma. Blood 108(6):2020–2028. doi: 10.1182/blood-2005-11-013458 PubMedCrossRefGoogle Scholar
  27. 27.
    Tibshirani R, Hastie T, Narasimhan B, Chu G (2002) Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci USA 99(10):6567–6572. doi: 10.1073/pnas.082099299 PubMedCrossRefGoogle Scholar
  28. 28.
    Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, Stewart JP, Kordsmeier B, Randolph C, Williams DR, Xiao Y, Xu H, Epstein J, Anaissie E, Krishna SG, Cottler-Fox M, Hollmig K, Mohiuddin A, Pineda-Roman M, Tricot G, van Rhee F, Sawyer J, Alsayed Y, Walker R, Zangari M, Crowley J, Barlogie B (2007) A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109(6):2276–2284. doi: 10.1182/blood-2006-07-038430 PubMedCrossRefGoogle Scholar
  29. 29.
    Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B, Stewart JP, Zhan F, Khatry D, Protopopova M, Protopopov A, Sukhdeo K, Hanamura I, Stephens O, Barlogie B, Anderson KC, Chin L, Shaughnessy JD Jr, Brennan C, Depinho RA (2006) High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9(4):313–325. doi: 10.1016/j.ccr.2006.03.019 PubMedCrossRefGoogle Scholar
  30. 30.
    Fabris S, Ronchetti D, Agnelli L, Baldini L, Morabito F, Bicciato S, Basso D, Todoerti K, Lombardi L, Lambertenghi-Deliliers G, Neri A (2007) Transcriptional features of multiple myeloma patients with chromosome 1q gain. Leukemia 21(5):1113–1116. doi: 10.1038/sj.leu.2404616 PubMedGoogle Scholar
  31. 31.
    Condomines M, Hose D, Raynaud P, Hundemer M, De Vos J, Baudard M, Moehler T, Pantesco V, Moos M, Schved JF, Rossi JF, Reme T, Goldschmidt H, Klein B (2007) Cancer/testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis. J Immunol 178(5):3307–3315PubMedGoogle Scholar
  32. 32.
    Hose D, Reme T, Meissner T, Moreaux J, Seckinger A, Lewis J, Benes V, Benner A, Hundemer M, Hielscher T, Shaughnessy JD Jr, Barlogie B, Neben K, Kramer A, Hillengass J, Bertsch U, Jauch A, De Vos J, Rossi JF, Mohler T, Blake J, Zimmermann J, Klein B, Goldschmidt H (2009) Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood 113(18):4331–4340. doi: 10.1182/blood-2008-09-178350 PubMedCrossRefGoogle Scholar
  33. 33.
    Hose D, Reme T, Hielscher T, Moreaux J, Messner T, Seckinger A, Benner A, Shaughnessy JD Jr, Barlogie B, Zhou Y, Hillengass J, Bertsch U, Neben K, Mohler T, Rossi JF, Jauch A, Klein B, Goldschmidt H (2011) Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica 96(1):87–95. doi: 10.3324/haematol.2010.030296 PubMedCrossRefGoogle Scholar
  34. 34.
    Decaux O, Lode L, Magrangeas F, Charbonnel C, Gouraud W, Jezequel P, Attal M, Harousseau JL, Moreau P, Bataille R, Campion L, Avet-Loiseau H, Minvielle S (2008) Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol 26(29):4798–4805. doi: 10.1200/JCO.2007.13.8545 PubMedCrossRefGoogle Scholar
  35. 35.
    Chng WJ, Kumar S, Vanwier S, Ahmann G, Price-Troska T, Henderson K, Chung TH, Kim S, Mulligan G, Bryant B, Carpten J, Gertz M, Rajkumar SV, Lacy M, Dispenzieri A, Kyle R, Greipp P, Bergsagel PL, Fonseca R (2007) Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 67(7):2982–2989. doi: 10.1158/0008-5472.CAN-06-4046 PubMedCrossRefGoogle Scholar
  36. 36.
    Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S, Koenig E, Fergus A, Huang Y, Richardson P, Trepicchio WL, Broyl A, Sonneveld P, Shaughnessy JD Jr, Bergsagel PL, Schenkein D, Esseltine DL, Boral A, Anderson KC (2007) Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 109(8):3177–3188. doi: 10.1182/blood-2006-09-044974 PubMedCrossRefGoogle Scholar
  37. 37.
    Agnelli L, Forcato M, Ferrari F, Tuana G, Todoerti K, Walker BA, Morgan GJ, Lombardi L, Bicciato S, Neri A (2011) The reconstruction of transcriptional networks reveals critical genes with implications for clinical outcome of multiple myeloma. Clin Cancer Res 17(23):7402–7412. doi: 10.1158/1078-0432.CCR-11-0596 PubMedCrossRefGoogle Scholar
  38. 38.
    Margolin AA, Wang K, Lim WK, Kustagi M, Nemenman I, Califano A (2006) Reverse engineering cellular networks. Nat Protoc 1(2):662–671. doi: 10.1038/nprot.2006.106 PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou Y, Barlogie B, Shaughnessy JD Jr (2009) The molecular characterization and clinical management of multiple myeloma in the post-genome era. Leukemia 23(11):1941–1956. doi: 10.1038/leu.2009.160 PubMedCrossRefGoogle Scholar
  40. 40.
    Mahtouk K, Hose D, De Vos J, Moreaux J, Jourdan M, Rossi JF, Reme T, Goldschmidt H, Klein B (2007) Input of DNA microarrays to identify novel mechanisms in multiple myeloma biology and therapeutic applications. Clin Cancer Res 13(24):7289–7295. doi: 10.1158/1078-0432.CCR-07-1758 PubMedCrossRefGoogle Scholar
  41. 41.
    Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644–648. doi: 10.1126/science.1117679 PubMedCrossRefGoogle Scholar
  42. 42.
    Fabris S, Agnelli L, Mattioli M, Baldini L, Ronchetti D, Morabito F, Verdelli D, Nobili L, Intini D, Callea V, Stelitano C, Lombardi L, Neri A (2005) Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses. Genes Chromosomes Cancer 42(2):117–127. doi: 10.1002/gcc.20123 PubMedCrossRefGoogle Scholar
  43. 43.
    Chari R, Thu KL, Wilson IM, Lockwood WW, Lonergan KM, Coe BP, Malloff CA, Gazdar AF, Lam S, Garnis C, MacAulay CE, Alvarez CE, Lam WL (2010) Integrating the multiple dimensions of genomic and epigenomic landscapes of cancer. Cancer Metastasis Rev 29(1):73–93. doi: 10.1007/s10555-010-9199-2 PubMedCrossRefGoogle Scholar
  44. 44.
    Largo C, Alvarez S, Saez B, Blesa D, Martin-Subero JI, Gonzalez-Garcia I, Brieva JA, Dopazo J, Siebert R, Calasanz MJ, Cigudosa JC (2006) Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma. Haematologica 91(2):184–191PubMedGoogle Scholar
  45. 45.
    Lombardi L, Poretti G, Mattioli M, Fabris S, Agnelli L, Bicciato S, Kwee I, Rinaldi A, Ronchetti D, Verdelli D, Lambertenghi-Deliliers G, Bertoni F, Neri A (2007) Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. Genes Chromosomes Cancer 46(3):226–238. doi: 10.1002/gcc.20404 PubMedCrossRefGoogle Scholar
  46. 46.
    Cigudosa JC, Rao PH, Calasanz MJ, Odero MD, Michaeli J, Jhanwar SC, Chaganti RS (1998) Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization. Blood 91(8):3007–3010PubMedGoogle Scholar
  47. 47.
    Cremer FW, Bila J, Buck I, Kartal M, Hose D, Ittrich C, Benner A, Raab MS, Theil AC, Moos M, Goldschmidt H, Bartram CR, Jauch A (2005) Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes Chromosomes Cancer 44(2):194–203. doi: 10.1002/gcc.20231 PubMedCrossRefGoogle Scholar
  48. 48.
    Gutierrez NC, Garcia JL, Hernandez JM, Lumbreras E, Castellanos M, Rasillo A, Mateo G, Perez S, Orfao A, San Miguel JF (2004) Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood 104(9):2661–2666. doi: 10.1182/blood-2004-04-1319 PubMedCrossRefGoogle Scholar
  49. 49.
    Lai JL, Zandecki M, Mary JY, Bernardi F, Izydorczyk V, Flactif M, Morel P, Jouet JP, Bauters F, Facon T (1995) Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood 85(9):2490–2497PubMedGoogle Scholar
  50. 50.
    Liebisch P, Viardot A, Bassermann N, Wendl C, Roth K, Goldschmidt H, Einsele H, Straka C, Stilgenbauer S, Dohner H, Bentz M (2003) Value of comparative genomic hybridization and fluorescence in situ hybridization for molecular diagnostics in multiple myeloma. Br J Haematol 122(2):193–201PubMedCrossRefGoogle Scholar
  51. 51.
    Nilsson T, Hoglund M, Lenhoff S, Rylander L, Turesson I, Westin J, Mitelman F, Johansson B (2003) A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences. Br J Haematol 120(6):960–969PubMedCrossRefGoogle Scholar
  52. 52.
    Agnelli L, Fabris S, Bicciato S, Basso D, Baldini L, Morabito F, Verdelli D, Todoerti K, Lambertenghi-Deliliers G, Lombardi L, Neri A (2007) Upregulation of translational machinery and distinct genetic subgroups characterise hyperdiploidy in multiple myeloma. Br J Haematol 136(4):565–573. doi: 10.1111/j.1365-2141.2006.06467.x PubMedCrossRefGoogle Scholar
  53. 53.
    Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL, Attal M, Marit G, Mathiot C, Facon T, Moreau P, Anderson KC, Campion L, Munshi NC, Minvielle S (2009) Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol 27(27):4585–4590. doi: 10.1200/JCO.2008.20.6136 PubMedCrossRefGoogle Scholar
  54. 54.
    Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, Johnson DC, Gonzalez D, Dagrada GP, Protheroe RK, Konn ZJ, Stockley DM, Gregory WM, Davies FE, Ross FM, Morgan GJ (2010) A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood 116(15):e56–e65. doi: 10.1182/blood-2010-04-279596 PubMedCrossRefGoogle Scholar
  55. 55.
    Agnelli L, Mosca L, Fabris S, Lionetti M, Andronache A, Kwee I, Todoerti K, Verdelli D, Battaglia C, Bertoni F, Deliliers GL, Neri A (2009) A SNP microarray and FISH-based procedure to detect allelic imbalances in multiple myeloma: an integrated genomics approach reveals a wide gene dosage effect. Genes Chromosomes Cancer 48(7):603–614. doi: 10.1002/gcc.20668 PubMedCrossRefGoogle Scholar
  56. 56.
    Walker BA, Leone PE, Jenner MW, Li C, Gonzalez D, Johnson DC, Ross FM, Davies FE, Morgan GJ (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. doi: 10.1182/blood-2006-02-005496 PubMedCrossRefGoogle Scholar
  57. 57.
    Jenner MW, Leone PE, Walker BA, Ross FM, Johnson DC, Gonzalez D, Chiecchio L, Dachs Cabanas E, Dagrada GP, Nightingale M, Protheroe RK, Stockley D, Else M, Dickens NJ, Cross NC, Davies FE, Morgan GJ (2007) Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. Blood 110(9):3291–3300. doi: 10.1182/blood-2007-02-075069 PubMedCrossRefGoogle Scholar
  58. 58.
    Lionetti M, Biasiolo M, Agnelli L, Todoerti K, Mosca L, Fabris S, Sales G, Deliliers GL, Bicciato S, Lombardi L, Bortoluzzi S, Neri A (2009) Identification of microRNA expression patterns and definition of a microRNA/mRNA regulatory network in distinct molecular groups of multiple myeloma. Blood 114(25):e20–e26. doi: 10.1182/blood-2009-08-237495 PubMedCrossRefGoogle Scholar
  59. 59.
    Dickens NJ, Walker BA, Leone PE, Johnson DC, Brito JL, Zeisig A, Jenner MW, Boyd KD, Gonzalez D, Gregory WM, Ross FM, Davies FE, Morgan GJ (2010) Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clin Cancer Res 16(6):1856–1864. doi: 10.1158/1078-0432.CCR-09-2831 PubMedCrossRefGoogle Scholar
  60. 60.
    Largo C, Saez B, Alvarez S, Suela J, Ferreira B, Blesa D, Prosper F, Calasanz MJ, Cigudosa JC (2007) Multiple myeloma primary cells show a highly rearranged unbalanced genome with amplifications and homozygous deletions irrespective of the presence of immunoglobulin-related chromosome translocations. Haematologica 92(6):795–802PubMedCrossRefGoogle Scholar
  61. 61.
    Broderick P, Chubb D, Johnson DC, Weinhold N, Forsti A, Lloyd A, Olver B, Ma YP, Dobbins SE, Walker BA, Davies FE, Gregory WA, Child JA, Ross FM, Jackson GH, Neben K, Jauch A, Hoffmann P, Muhleisen TW, Nothen MM, Moebus S, Tomlinson IP, Goldschmidt H, Hemminki K, Morgan GJ, Houlston RS (2012) Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet 44(1):58–61. doi: 10.1038/ng.993 CrossRefGoogle Scholar
  62. 62.
    Heller G, Schmidt WM, Ziegler B, Holzer S, Mullauer L, Bilban M, Zielinski CC, Drach J, Zochbauer-Muller S (2008) Genome-wide transcriptional response to 5-aza-2′-deoxycytidine and trichostatin a in multiple myeloma cells. Cancer Res 68(1):44–54. doi: 10.1158/0008-5472.CAN-07-2531 PubMedCrossRefGoogle Scholar
  63. 63.
    Smith EM, Boyd K, Davies FE (2010) The potential role of epigenetic therapy in multiple myeloma. Br J Haematol 148(5):702–713. doi: 10.1111/j.1365-2141.2009.07976.x PubMedCrossRefGoogle Scholar
  64. 64.
    Chim CS, Liang R, Leung MH, Kwong YL (2007) Aberrant gene methylation implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. J Clin Pathol 60(1):104–106. doi: 10.1136/jcp.2006.036715 PubMedCrossRefGoogle Scholar
  65. 65.
    Chim CS, Kwong YL, Fung TK, Liang R (2004) Methylation profiling in multiple myeloma. Leuk Res 28(4):379–385. doi: 10.1016/j.leukres.2003.08.008 PubMedCrossRefGoogle Scholar
  66. 66.
    Salhia B, Baker A, Ahmann G, Auclair D, Fonseca R, Carpten J (2010) DNA methylation analysis determines the high frequency of genic hypomethylation and low frequency of hypermethylation events in plasma cell tumors. Cancer Res 70(17):6934–6944. doi: 10.1158/0008-5472.CAN-10-0282 PubMedCrossRefGoogle Scholar
  67. 67.
    Bollati V, Fabris S, Pegoraro V, Ronchetti D, Mosca L, Deliliers GL, Motta V, Bertazzi PA, Baccarelli A, Neri A (2009) Differential repetitive DNA methylation in multiple myeloma molecular subgroups. Carcinogenesis 30(8):1330–1335. doi: 10.1093/carcin/bgp149 PubMedCrossRefGoogle Scholar
  68. 68.
    Walker BA, Wardell CP, Chiecchio L, Smith EM, Boyd KD, Neri A, Davies FE, Ross FM, Morgan GJ (2011) Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. Blood 117(2):553–562. doi: 10.1182/blood-2010-04-279539 PubMedCrossRefGoogle Scholar
  69. 69.
    Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12(12):861–874. doi: 10.1038/nrg3074 PubMedCrossRefGoogle Scholar
  70. 70.
    Pichiorri F, De Luca L, Aqeilan RI (2011) MicroRNAs: new players in multiple myeloma. Front Genet 2:22. doi: 10.3389/fgene.2011.00022 PubMedGoogle Scholar
  71. 71.
    Ronchetti D, Lionetti M, Mosca L, Agnelli L, Andronache A, Fabris S, Deliliers GL, Neri A (2008) An integrative genomic approach reveals coordinated expression of intronic miR-335, miR-342, and miR-561 with deregulated host genes in multiple myeloma. BMC Med Genomics 1:37. doi: 10.1186/1755-8794-1-37 PubMedCrossRefGoogle Scholar
  72. 72.
    Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, Taccioli C, Zanesi N, Alder H, Hagan JP, Munker R, Volinia S, Boccadoro M, Garzon R, Palumbo A, Aqeilan RI, Croce CM (2008) MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 105(35):12885–12890. doi: 10.1073/pnas.0806202105 PubMedCrossRefGoogle Scholar
  73. 73.
    Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F, Runnels J, Jia X, Ngo HT, Melhem MR, Lin CP, Ribatti D, Rollins BJ, Witzig TE, Anderson KC, Ghobrial IM (2009) MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood 113(26):6669–6680. doi: 10.1182/blood-2009-01-198408 PubMedCrossRefGoogle Scholar
  74. 74.
    Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, Rajewsky N, Bender TP, Rajewsky K (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131(1):146–159. doi: 10.1016/j.cell.2007.07.021 PubMedCrossRefGoogle Scholar
  75. 75.
    Faraoni I, Antonetti FR, Cardone J, Bonmassar E (2009) miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 1792(6):497–505. doi: 10.1016/j.bbadis.2009.02.013 PubMedCrossRefGoogle Scholar
  76. 76.
    Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N (2005) Combinatorial microRNA target predictions. Nat Genet 37(5):495–500. doi: 10.1038/ng1536 PubMedCrossRefGoogle Scholar
  77. 77.
    Gutierrez NC, Sarasquete ME, Misiewicz-Krzeminska I, Delgado M, De Las Rivas J, Ticona FV, Ferminan E, Martin-Jimenez P, Chillon C, Risueno A, Hernandez JM, Garcia-Sanz R, Gonzalez M, San Miguel JF (2010) Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling. Leukemia 24(3):629–637. doi: 10.1038/leu.2009.274 PubMedCrossRefGoogle Scholar
  78. 78.
    Xiao F, Zuo Z, Cai G, Kang S, Gao X, Li T (2009) miRecords: an integrated resource for microRNA-target interactions. Nucleic Acids Res 37(Database issue):D105–D110. doi: 10.1093/nar/gkn851 PubMedCrossRefGoogle Scholar
  79. 79.
    Zhou Y, Chen L, Barlogie B, Stephens O, Wu X, Williams DR, Cartron MA, van Rhee F, Nair B, Waheed S, Pineda-Roman M, Alsayed Y, Anaissie E, Shaughnessy JD Jr (2010) High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2. Proc Natl Acad Sci USA 107(17):7904–7909. doi: 10.1073/pnas.0908441107 PubMedCrossRefGoogle Scholar
  80. 80.
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550. doi: 10.1073/pnas.0506580102 PubMedCrossRefGoogle Scholar
  81. 81.
    Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ, Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Stewart AK, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, Getz G, Golub TR (2011) Initial genome sequencing and analysis of multiple myeloma. Nature 471(7339):467–472. doi: 10.1038/nature09837 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly
  2. 2.Ematology 1CTMO, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly

Personalised recommendations