Cancer Genetics
Volume 204, Issue 1 , Pages 3-12 , January 2011

The prognostic significance of cytogenetics and molecular profiling in multiple myeloma

Received 1 November 2010 ,Accepted 1 November 2010.

References 

  1. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175–187
  2. Raab MS, Podar K, Breitkreutz I, et al. Multiple Myeloma. Lancet. 2009;374:324–339
  3. Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In:  Kaushansky K,  Lichtman MA,  Beutler E, et al. editor. Williams Hematology. 7th edition. New York: McGraw-Hill Professional; 2005;p. 1501–1533
  4. DeWald GW, Kyle RA, Hicks GA, Greipp PR. The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood. 1985;66:380–390
  5. Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet. 1995;82:41–49
  6. Lai JL, Zandecki M, Mary JY, et al. Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood. 1995;85:2490–2497
  7. Smadja NV, Louvet C, Isnard F, et al. Cytogenetic study in multiple myeloma at diagnosis: comparison of two techniques. Br J Haematol. 1995;90:619–624
  8. Calasanz MJ, Cigudosa JC, Odero MD, et al. Cytogenetic analysis of 280 patients with multiple myeloma and related disorders; primary breakpoints and clinical correlations. Genes Chrom Cancer. 1997;18:84–93
  9. Seong C, Delasalle K, Hayes K, et al. Prognostic value of cytogenetics in multiple myeloma. Br J Heamtol. 1998;101:189–194
  10. Rajkumar SV, Fonseca R, Dewald GW, et al. Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma. Cancer Genet Cytogenet. 1999;113:73–77
  11. Zhan F, Sawyer J, Tricot G. The role of cytogenetics in myeloma. Leukemia. 2006;20:1484–1486
  12. Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene. 2001;20:5611–5622
  13. Gabrea A, Martelli ML, Qi Y, et al. Secondary genomic rearrangements involving immunoglobulin or MYC loci show similar prevalences in hyperdiploid and non-hyperdiploid myeloma tumors. Genes Chromosomes Cancer. 2008;47:573–590
  14. Dao D, Sawyer J, Esptein J, et al. Deletion of retinoblastoma gene in multiple myeloma. Leukemia. 1994;8:1280–1284
  15. Drach J, Angerler J, Schuster J, et al. Interphase fluorescence in situ hybridization identifies chromosome abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood. 1995;86:3915–3921
  16. Drach J, Schuster J, Nowotny H, et al. Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Res. 1995;55:3854–3859
  17. Zandecki M, Lai JL, Genevieve F, et al. Several cytogenetic subclones may be identified with plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood. 1997;90:3682–3690
  18. Rao PH, Cigudos J, Ning Y, et al. Karyotypic complexity of multiple myeloma defined by multicolor spectral karyotyping. Blood. 1998;92:1743–1748
  19. Sawyer JR, Lukacs JL, Munshi N, et al. Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping. Blood. 1998;92:4249–4278
  20. Sawyer JR, Lukacs JL, Thomas EL, et al. Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma. Br J Haematol. 2001;112:167–174
  21. Cigudosa JC, Rao PH, Calasanz MJ, et al. Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization. Blood. 1998;91:3007–3010
  22. Avet-Loiseau H, Andree-Ashley LE, Moore D, et al. Molecular cytogenetic abnormalities in multiple myeloma and plasma cell leukemia measured using comparative genomic hybridization. Genes Chromosomes Cancer. 1997;19:124–133
  23. Gutierrez NC, Garica JL, Hernandez JM, et al. Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood. 2004;104:2161–2166
  24. Dewald GW, Therneau T, Larson D, et al. Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma. Blood. 2005;106:3553–3558
  25. Kapoor P, Fonseca R, Rajkumar SV, et al. Evidence for cytogenetic and fluorescence in situ hybridization risk stratification of newly diagnosed multiple myeloma in the era of novel therapies. Mayo Clin Proc. 2010;85:532–537
  26. Nilsson T, Höglund M, Lenhoff S, et al. A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved segments as well as significant age-and sex-related differences. Br J Haematol. 2003;120:960–969
  27. Chng WJ, Ketterling RP, Fonseca R. Analysis of genetic abnormalities provides insights into genetic evolution of hyperdiploid myeloma. Genes Chromosomes Cancer. 2006;45:1111–1120
  28. Smadja NV, Bastard C, Brigaudeau C, et al. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001;98:2229–2238
  29. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546–1558
  30. Smadja NV, Fruchart C, Isnard F, et al. Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia. 1998;12:960–969
  31. Tonon G. Molecular pathogenesis of multiple myeloma. Hematol Oncol Clin N Am. 2007;21:985–1006
  32. Bergsagel PL, Chesi M, Nardini E, et al. Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA. 1996;93:13931–13936
  33. Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol. 2005;23:6333–6338
  34. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group International Myeloma Working Group molecular classification of multiple myeloma: spot light review. Leukemia. 2009;23:2210–2221
  35. Fonseca R, Blood EA, Oken MM, et al. Myeloma and the t(11;14)(q13;q32): evidence for a biologically defined unique subset of patients. Blood. 2002;99:3735–3741
  36. Chesi M, Nardini E, Lim RS, et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998;92:3025–3034
  37. Santra M, Zhan F, Tian E, et al. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood. 2003;101:2374–2376
  38. Keats JJ, Reiman T, Maxwell CA, et al. In multiple myeloma t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003;101:1520–1529
  39. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569–4575
  40. Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005;106:2837–2840
  41. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007;109:3489–3495
  42. Avet-Loiseau H, Facon T, Daviet A, et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome. Cancer Res. 1999;59:4546–4550
  43. Jenner MW, Leone PE, Walker BA, et al. 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. 2007;110:3291–3300
  44. Avet-Loiseau H, Gerson F, Magrangeas F, et al. Intergroupe Francophone du Myélome. Rearrangements of c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood. 2001;98:3082–3086
  45. Tricot G, Barlogie B, Jagannath S, et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood. 1995;86:4250–4256
  46. Tricot G, Sawyer JR, Jagannath S, et al. Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants. J Clin Oncol. 1997;15:2659–2666
  47. Pérez-Simón JA, Garcia-Sanz R, Tabernero MD, et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood. 1998;91:3366–3371
  48. Avet-Loiseau H, Daviet A, Saunier S, Bataille R. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol. 2000;111:1116–1117
  49. Fonseca R, Oken MM, Harrington D, et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia. 2001;15:981–986
  50. Shaughnessy JD, Tian E, Sawyer J, et al. High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Blood. 2000;96:1505–1511
  51. Zhou Y, Barlogie B, Shaughnessy JD. The molecular characterization and clinical management of multiple myeloma in the post-genome era. Leukemia. 2009;23:1941–1956
  52. Neri A, Baldini L, Trecca D, et al. p53 gene mutation in multiple myeloma are associated with advanced forms of malignancy. Blood. 1993;81:128–135
  53. Corradini P, Inghirami G, Astolfi M. Inactivation of tumor suppressor genes, p53, and Rb1 in plasma cell dyscrasias. Leukemia. 1994;8:758–767
  54. Owen RG, Davis SA, Randerson J, et al. p53 gene mutation in multiple myeloma. Mol Pathol. 1997;50:18
  55. Drach J, Ackermann J, Fritz E, et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood. 1998;92:802–809
  56. Cremer FW, Bila J, Buck I, et al. Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes Chrom Cancer. 2005;44:194–203
  57. Le Baccon P, Leroux D, Dascalescu C, et al. Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma. Genes Chrom Cancer. 2001;32:250–264
  58. Sawyer JR, Tricot G, Lukacs JL, et al. Genomic instability in multiple myeloma: evidence for jumping segmental duplications of chromosome arm 1q. Genes Chromosomes Cancer. 2005;42:95–106
  59. Debes-Marun CS, Dewald GW, Bryant S, et al. Chromosome abnormalities clustering and its implication for pathogenesis and prognosis in myeloma. Leukemia. 2003;17:427–436
  60. Qazilbash MH, Saliba RM, Ahmed B, et al. Deletion of the short arm of chromosome 1(del1p) is a strong predictor of poor outcome in myeloma patients undergoing an autotransplant. Biol Blood Marrow Transplant. 2007;13:1066–1072
  61. Wu KL, Beverloo B, Lokhorst HM, et al. Dutch-Belgian Haemato-Oncology Cooperative Study Group, Dutch Working Party on Cancer Genetics and Cytogenetics. Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor of the outcome of high-dose chemotherapy in patients with multiple myeloma. Br J Haematol. 2007;136:615–623
  62. Chang H, Ning Y, Qi X, et al. Chromosome 1p21 deletion is a novel prognostic marker in patients with multiple myeloma. Br J Haematol. 2007;139:51–54
  63. Walker BA, Leone PE, Chiecchio L, et al. A compendium of myeloma associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116:56–65
  64. Hanamura I, Stewart JP, Huang Y, et al. 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 transplantations. Blood. 2006;108:1724–1732
  65. Chang H, Yeung J, Xu W, et al. Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridization. Br J Haematol. 2006;134:613–615
  66. Treon SP, Maimonis P, Bua D, et al. Elevated soluble MUC1 levels and decreased anti-MUC1 antibody levels in patients with multiple myeloma. Blood. 2000;96:3147–3153
  67. Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 2002;99:1885–1893
  68. Inoue J, Otsuki T, Hirasawa A, et al. Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. Am J Pathol. 2004;165:71–81
  69. Shaughnessy J. 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. 2005;10:117–126
  70. Chang H, Qi X, Trieu Y, Xu W, Reader JC, Ning Y, et al. Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation. Br J Haematol. 2006;135:486–491
  71. Carrasco DR, Tonon G, Huang Y, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;4:313–325
  72. Walker BA, Leone PE, Jenner MW, et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood. 2006;108:1733–1743
  73. Shaughnessy JD, Zhan F, Burington BE, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109:2276–2284
  74. Zhan F, Colla S, Wu X, et al. CKS1B, over expressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1- dependent and -independent mechanisms. Blood. 2007;109:4995–5001
  75. Fabris S, Ronchetti D, Agnelli L, et al. Transcriptional features of multiple myeloma patients with chromosome 1q gain. Leukemia. 2007;21:1113–1116
  76. Decaux O, Lodé L, Magrangeas F, et al. Intergroupe Francophone du Myélome. 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 Myélome. J Clin Oncol. 2008;26:798–805
  77. Lestou VS, Gascoyne RD, Salski C, et al. Uncovering novel inter-and intrachromosomal chromosome 1 aberrations in follicular lymphomas by using an innovative multicolor banding technique. Genes Chromosomes Cancer. 2002;34:201–210
  78. Itoyama T, Nanjungud G, Chen W, et al. Molecular cytogenetic analysis of genomic instability at the 1q12-22 chromosomal site in B-cell non-Hodgkin lymphoma. Genes Chrom Cancer. 2002;35:318–328
  79. Sawyer JR, Tricot G, Mattox S, et al. Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood. 1998;91:1732–1741
  80. Sawyer JR, Tian E, Thomas E, et al. Evidence for a novel mechanism for gene amplification in multiple myeloma: 1q12 pericentromeric heterochromatin mediates breakage-fusion-bridge cycles of a 1q12∼q23 amplicon. Br J Haematol. 2009;147:484–494
  81. Berger R, Bernard OA. Jumping translocations. Genes Chromosomes Cancer. 2007;46:717–723
  82. Fournier A, Florin A, Lefebvre C, et al. Genetics and epigenetics of 1q rearrangements in hematological malignancies. Cytogenet Genome Res. 2007;118:320–327
  83. Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol. 2007;20:571–596
  84. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194:23–28
  85. Olney HJ, Le Beau MM. Myelodysplastic syndromes. In:  Heim S,  Mitleman F editor. Cancer Cytogenetics. 3rd edition. Hoboken, NJ: John Wiley and Sons; 2009;p. 141–178
  86. Nilsson T, Nilsson L, Lenhoff S, et al. MDS/AML-associated cytogenetic abnormalities in multiple myeloma and monoclonal gammopathy of undetermined significance: evidence for frequent de novo occurrence and multipotent stem cell involvement of del(20q). Genes Chromosomes Cancer. 2004;41:223–231
  87. Govindarajan R, Jagannath S, Flick JT, et al. Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol. 1996;95:349–353
  88. Jacobson J, Barlogie B, Shaughnessy J, et al. MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants. Br J Haematol. 2003;122:430–440
  89. Barlogie B, Tricot G, Haessler J, et al. Cytogenetically-defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3,000 patients treated since 1989. Blood. 2008;111:94–100
  90. Maciejewski JP, Mufti J. Whole genome scanning as a cytogenetic tool in hematologic malignancies. Blood. 2008;112:965–974
  91. Claudio JO, Masih-Khan E, Tang H, et al. A molecular compendium of genes expressed in multiple myeloma. Blood. 2002;100:2175–2186
  92. Magrangeas F, Nasser V, Avet-Loiseau H, et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood. 2003;101:4998–5006
  93. Dring AM, Davies EE, Fenton JA, et al. A global expression-based analysis of the consequences of the t(4;14) on myeloma. Clin Cancer Res. 2004;10:5692–5701
  94. Bergsagel PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303
  95. Angelli L, Bicciato S, Mattioli M, et al. Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. J Clin Oncol. 2005;23:7296–7306
  96. Zhan F, Huang Y, Colla S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020–2028
  97. Agnelli L, Fabris S, Bicciato S, et al. Upregulation of translational machinery and distinct genetic subgroups characterise hyperdiploidy in multiple myeloma. Br J Haematol. 2007;136:565–573
  98. Mahtouk K, Hose D, De Vos J, et al. Input of DNA microarrays to identify novel mechanisms in multiple myeloma biology and therapeutic applications. Clin Cancer Res. 2007;13:7289–7295
  99. Chng WJ, Kumar S, Vanwier S, et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 2007;67:2982–2989
  100. Agnelli L, Mosca I, Fabris S, et al. 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. 2009;48:603–614
  101. Chng WJ, Gertz MA, Chung TH, et al. Correlation between array-comparative genomic hybridization-defined genomic gains and losses and survival: identification of 1p31-32 deletion as a prognostic factor in myeloma. Leukemia. 2010;24:833–842
  102. Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;27:4585–4590

PII: S0165-4608(10)00564-9

doi: 10.1016/j.cancergencyto.2010.11.002

Cancer Genetics
Volume 204, Issue 1 , Pages 3-12 , January 2011