Abstract
Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations’ control to eradicate all myeloma subclones in order to obtain long-term remission.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.
Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370: 1209–1218.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906–917.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 2010; 28: 4621–4629.
Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010; 11: 29–37.
Greaves M, Maley CC . Clonal evolution in cancer. Nature 2012; 481: 306–313.
Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23: 2210–2221.
Walker BA, Leone PE, Jenner MW, Li C, Gonzalez D, Johnson DC 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.
Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol 2009; 27: 4585–4590.
Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features and clinical presentation. Blood 2002; 99: 2185–2191.
Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C . dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 2004; 20: 1233–1240.
Rozen S, Skaletsky HJ . Bioinformatics methods and protocols. In Krawetz S, Misener S, (eds) Methods in Molecular Biology. Humana Press: Totowa, NJ, pp 365–386, 2000.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.
Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332–2336.
Jakubikova J, Adamia S, Kost-Alimova M, Klippel S, Cervi D, Daley JF et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood 2011; 117: 4409–4419.
Hastings PJ, Ira G, Lupski JR . A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 2009; 5: e1000327.
Hastings PJ, Lupski JR, Rosenberg SM, Ira G . Mechanisms of change in gene copy number. Nat Rev Genet 2009; 10: 551–564.
Conrad DF, Bird C, Blackburne B, Lindsay S, Mamanova L, Lee C et al. Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 2010; 42: 385–391.
Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12: 115–130.
Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12: 131–144.
Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012; 120: 1067–1076.
Egan JB, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S et al. Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides. Blood 2012; 120: 1060–1066.
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.
Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.
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.
Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 2011; 469: 362–367.
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481: 506–510.
Lopez-Corral L, Gutiérrez NC, Vidriales MB, Mateos MV, Rasillo A, García-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.
Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR 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 transplantation. Blood 2006; 108: 1724–1732.
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.
Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011; 471: 467–472.
Morgan GJ, Walker BA, Davies FE . The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12: 335–348.
Munshi NC, Anderson KC, Bergsagel PL, Shaughnessy J, Palumbo A, Durie B et al. International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 2011; 117: 4696–4700.
Acknowledgements
This study was supported by IFM; the French National Research Agency, Grant R08079NS (to SM); the French Institute National du Cancer, Grant R09076NN (to HA-L); the National Institutes of Health, Grants PO1 CA155258-01 (to NCM, SM, HA-L and KCA), RO1-124929 (to NCM), P50-100007 and PO1-78378 (to NCM and KCA), and Department of Veterans Affairs Merit Review Awards. We thank Elise Douillard, Magali Devic, Emilie Maurenton and Nathalie Roi for excellent technical expertise. We also thank Marie C Béné for critical reading of the manuscript.
Author contributions
PM, OD, PG, LG, LV, TF, AMS, GM, CH, PC, MT, EV, ER and HA-L provided study materials or patients, and collected clinical follow-up data. FM, LL, HA-L, WG and SM analyzed the data. FM, HA-L, NCM, KCA and SM designed the study. SM and FM wrote the report. All investigators reviewed the final report.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Leukemia website
Supplementary information
Rights and permissions
About this article
Cite this article
Magrangeas, F., Avet-Loiseau, H., Gouraud, W. et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia 27, 473–481 (2013). https://doi.org/10.1038/leu.2012.226
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2012.226
Keywords
This article is cited by
-
Identification of a cholesterol metabolism-related prognostic signature for multiple myeloma
Scientific Reports (2023)
-
The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
Nature Communications (2022)
-
Single-cell profiling of tumour evolution in multiple myeloma — opportunities for precision medicine
Nature Reviews Clinical Oncology (2022)
-
DNA hydroxymethylation is associated with disease severity and persists at enhancers of oncogenic regions in multiple myeloma
Clinical Epigenetics (2020)
-
Molecular basis of clonal evolution in multiple myeloma
International Journal of Hematology (2020)