Skip to main content
SpringerLink
Log in

Prognostic Implication of Genetic Changes (Cytogenetics, and FISH, Gains and Losses of DNA by SNP Array and aCGH) in Risk Stratification in Myeloma

  • Chapter
  • First Online:
Advances in Biology and Therapy of Multiple Myeloma

  • 800 Accesses

Abstract

Multiple myeloma (MM) is characterized by a huge heterogeneity in survival. Most of these differences can be captured by the variability of genetic events occurring within the malignant plasma cells. At the chromosomal level, the two most important changes are the del(17p) and the translocation t(4;14), both associated with a poor outcome. Recent data using modern genomics, such as gene expression profiling, or SNParray, revealed another level of complexity, which can be utilized for a better prognostic assessment. However, these techniques are still research tools. Whether there will be routine techniques in the future is an open question.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Avet-Loiseau H, Li C, Magrangeas F et al (2009) Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol 27:4585–4590

    Article  PubMed  CAS  Google Scholar 

  3. Dewald GW, Kyle RA, Hicks GA, Greipp PR (1985) The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia or amyloidosis. Blood 66:380–390

    PubMed  CAS  Google Scholar 

  4. Weh HJ, Gutensohn K, Selbach J et al (1993) Karyotype in multiple myeloma and plasma cell leukemia. Eur J Cancer 29A:1269–1273

    Article  PubMed  CAS  Google Scholar 

  5. Sawyer JR, Waldron JA, Jagannath S, Barlogie B (1995) Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 82:41–49

    Article  PubMed  CAS  Google Scholar 

  6. Laï JL, Zandecki M, Mary JY et al (1995) Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood 85:2490–2497

    PubMed  Google Scholar 

  7. Calasanz MJ, Cigudosa JC, Odero MD et al (1997) Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: Primary breakpoints and clinical correlations. Genes Chromosomes Cancer 18:84–93

    Article  PubMed  CAS  Google Scholar 

  8. Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C (2001) Hypodiploidy is a major prognostic factor in multiple myeloma. Blood 98:2229–2238

    Article  PubMed  CAS  Google Scholar 

  9. Drach J, Schuster J, Nowotny H et al (1995) Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Res 55:3854–3859

    PubMed  CAS  Google Scholar 

  10. Drach J, Angerler J, Schuster J et al (1995) Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood 86:3915–3921

    PubMed  CAS  Google Scholar 

  11. Zandecki M, Laï JL, Genevieve F et al (1997) Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood 90:3682–3690

    PubMed  CAS  Google Scholar 

  12. Nishida K, Tamura A, Nakazawa N et al (1997) The Ig heavy chain is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood 90:526–534

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Debes-Marun CS, Dewald GW, Bryant S et al (2003) Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia 17:427–436

    Article  PubMed  CAS  Google Scholar 

  15. Chng WJ, Winkler JM, Greipp PR et al (2006) Ploidy status rarely changes in myeloma patients at disease progression. Leuk Res 30:266–271

    Article  PubMed  CAS  Google Scholar 

  16. Wuillème S, Robillard N, Lodé L et al (2005) Ploidy, as detected by fluorescence in situ hybridization, defines different subgroups in multiple myeloma. Leukemia 19:275–278

    Article  PubMed  Google Scholar 

  17. Chng WJ, Van Wier SA, Ahmann GJ et al (2005) A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 106:2156–2161

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. 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. Blood 94:2583–2589

    PubMed  CAS  Google Scholar 

  20. Zojer N, Konigsberg R, Ackermann J et al (2000) Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 95:1925–1930

    PubMed  CAS  Google Scholar 

  21. Desikan R, Barlogie B, Sawyer J et al (2000) Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95:4008–4010

    PubMed  CAS  Google Scholar 

  22. Facon T, Avet-Loiseau H, Guillerm G et al (2001) Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 97:1566–1571

    Article  PubMed  CAS  Google Scholar 

  23. Fonseca R, Harrington D, Oken MM et al (2002) Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: An eastern cooperative oncology group study. Cancer Res 62:715–720

    PubMed  CAS  Google Scholar 

  24. Zhan F, Tian E, Bumm K et al (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 101:1128–1140

    Article  PubMed  CAS  Google Scholar 

  25. Agnelli L, Bicciato S, Fabris S et al (2007) Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma. Haematologica 92:56–65

    Article  PubMed  CAS  Google Scholar 

  26. Tricot G, Barlogie B, Jagannath S et al (1995) 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 86:4250–4256

    PubMed  CAS  Google Scholar 

  27. Shaughnessy J, Tian E, Sawyer J et al (2003) Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol 120:44–52

    Article  PubMed  Google Scholar 

  28. 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 20:1610–1617

    Article  PubMed  CAS  Google Scholar 

  29. Laï JL, Michaux L, Dastugue N et al (1998) Cytogenetics in multiple myeloma: a multicenter study of 24 patients with t(11;14)(q13;q32) or its variant. Cancer Genet Cytogenet 104:133–138

    Article  PubMed  Google Scholar 

  30. Fonseca R, Witzig TE, Gertz MA et al (1998) Multiple myeloma and the translocation t(11;14)(q13;q32): a report on 13 cases. Br J Haematol 101:296–301

    Article  PubMed  CAS  Google Scholar 

  31. Bergsagel PL, Chesi M, Nardini E et al (1996) Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA 93:13931–13936

    Article  PubMed  CAS  Google Scholar 

  32. Avet-Loiseau H, Facon T, Grosbois B et al (2002) Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features and clinical presentation. Blood 99:2185–2191

    Article  PubMed  CAS  Google Scholar 

  33. Fonseca R, Barlogie B, Bataille R et al (2004) Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64:1546–1558

    Article  PubMed  CAS  Google Scholar 

  34. Chesi M, Bergsagel PL, Brents LA et al (1996) Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88:674–681

    PubMed  CAS  Google Scholar 

  35. Janssen JWG, Vaandrager JW, Heuser T et al (2000) Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32). Blood 95:2691–2698

    PubMed  CAS  Google Scholar 

  36. Fonseca R, Blood EA, Oken MM et al (2002) Myeloma and the t(11;14)(q13;q32): evidence for a biologically defined unique subset of patients. Blood 99:3735–3741

    Article  PubMed  CAS  Google Scholar 

  37. Garand R, Avet-Loiseau R, Accard F et al (2003) t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma. Leukemia 17:2032–2035

    Article  PubMed  CAS  Google Scholar 

  38. Robillard N, Avet-Loiseau H, Garand R et al (2003) CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood 102:1070–1071

    Article  PubMed  CAS  Google Scholar 

  39. Moreau P, Facon T, Leleu X et al (2002) Recurrent 14q32 translocations determine the prognosis of multiple myeloma especially in patients receiving intensive chemotherapy. Blood 100:1579–1583

    Article  PubMed  CAS  Google Scholar 

  40. Gertz MA, Lacy MQ, Dispenzieri A et al (2005) 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 106:2837–2840

    Article  PubMed  CAS  Google Scholar 

  41. Chesi M, Nardini E, Brents LA et al (1997) Frequent Translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16:260–264

    Article  PubMed  CAS  Google Scholar 

  42. Chesi M, Nardini E, Lim RSC et al (1998) The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92:3025–3034

    PubMed  CAS  Google Scholar 

  43. Stec I, Wright TJ, Van Ommen GJ et al (1998) WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a drosophila dysmorphy gene maps in the Wolf-Hirschorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Hum Mol Genet 7:1071–1082

    Article  PubMed  CAS  Google Scholar 

  44. Plowright EE, Li Z, Bergsagel PL et al (2000) Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 9:992–998

    Google Scholar 

  45. Li Z, Zhu YX, Plowright EE et al (2001) The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 97:2413–2419

    Article  PubMed  CAS  Google Scholar 

  46. 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 101:1520–1529

    Article  PubMed  CAS  Google Scholar 

  47. Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy J (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 101:2374–2376

    Article  PubMed  CAS  Google Scholar 

  48. Moreau P, Attal M, Garban F et al (2007) Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia 21:2020–2024

    Article  PubMed  CAS  Google Scholar 

  49. 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  PubMed  CAS  Google Scholar 

  50. Chesi M, Bergsagel PL, Shonukan OO et al (1998) Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457–4463

    PubMed  CAS  Google Scholar 

  51. 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 5:191–199

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  53. 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 92:802–809

    PubMed  CAS  Google Scholar 

  54. Chang H, Qi C, Yi QL et al (2005) p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 105:358–360

    Article  PubMed  CAS  Google Scholar 

  55. Portier M, Moles JP, Mazars GR et al (1992) P53 and RAS gene mutations in multiple myeloma. Oncogene 7:2539–2543

    PubMed  CAS  Google Scholar 

  56. Preudhomme C, Facon T, Zandecki M et al (1992) Rare occurrence of P53 gene mutations in multiple myeloma. Br J Haematol 81:440–443

    Article  PubMed  CAS  Google Scholar 

  57. Chng WJ, Price-Troska T, Gonzalez-Paz N et al (2007) Clinical significance of TP53 mutation in myeloma. Leukemia 21:582–584

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  59. 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 108:1724–1732

    Article  PubMed  CAS  Google Scholar 

  60. Sawyer JR, Tricot G, Lukacs JL et al (2005) Genomic instability in multiple myeloma: evidence for jumping segmental duplications of chromosome arm 1q. Genes Chromosomes Cancer 42:95–106

    Article  PubMed  CAS  Google Scholar 

  61. Fonseca R, Van Wier SA, Chng WJ et al (2006) Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia 20:2034–2040

    Article  PubMed  CAS  Google Scholar 

  62. Cigudosa JC, Rao PH, Calasanz MJ et al (1998) Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization. Blood 91:3007–3010

    PubMed  CAS  Google Scholar 

  63. Liebisch P, Viardot A, Bassermann N et al (2003) Value of comparative genomic hybridization and fluorescence in situ hybridization for molecular diagnostics in multiple myeloma. Br J Haematol 122:193–201

    Article  PubMed  CAS  Google Scholar 

  64. Gutierrez NC, Garcia JL, Hernandez JM et al (2004) Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood 104:2661–2666

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  66. 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 12:115–130

    Article  PubMed  CAS  Google Scholar 

  67. 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 108:1733–1743

    Article  PubMed  CAS  Google Scholar 

  68. Jenner MW, Leone PE, Walker BA et al (2007) Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in clinical outcome in multiple myeloma. Blood 110:3291–3300

    Article  PubMed  CAS  Google Scholar 

  69. Walker BA, Leone PE, Chiecchio LA et al (2010) A compendium of myeloma associated chromosomal copy number abnormalities and their prognostic value. Blood 116(15):e56–e65

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unit for Genomics of Myeloma, CHU Rangueil, TSA 50032, 31059, Toulouse Cedex 9, France

    Jill Corre Pharm.D. & Hervé Avet-Loiseau M.D., Ph.D.

Authors
  1. Jill Corre Pharm.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hervé Avet-Loiseau M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hervé Avet-Loiseau M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Binney St. 44 44, Boston, 02115, Massachusetts, USA

    Nikhil C. Munshi

  2. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Kenneth C. Anderson

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Corre, J., Avet-Loiseau, H. (2013). Prognostic Implication of Genetic Changes (Cytogenetics, and FISH, Gains and Losses of DNA by SNP Array and aCGH) in Risk Stratification in Myeloma. In: Munshi, N., Anderson, K. (eds) Advances in Biology and Therapy of Multiple Myeloma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4666-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation