Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Exome sequencing in tracking clonal evolution in multiple myeloma following therapy

Leukemia volume 27, pages 1188–1191 (2013)Cite this article

Subjects

Sequencing the tumor genome using next-generation sequencing (NGS) is providing an unparalleled insight into the pathogenesis and progression of the disease. Much of the current focus of NGS in cancer is on defining mutations in the tumor genome at disease presentation, and these findings are central to understanding the molecular mechanisms that underlie pathogenesis. However, additional questions remain about the stability of the tumor clone under therapeutic pressure and these require a distinct second wave of NGS analyses. Understanding how each tumor evolves following therapy will be the key to delivering targeted therapy tailored for individual patients and in developing stratified therapeutic programs. Where a given tumor presents as a highly heterogeneous disease, this introduces a further complexity, requiring each subset of the disease to be evaluated separately in its response to therapy. Multiple myeloma (MM), defined as accumulation of malignant plasma cells in the bone marrow, exemplifies such a tumor and exhibits marked disease heterogeneity at presentation.1, 2 At the outset, aberrant chromosomal markers exist in diagnostic MM samples that are associated with poor prognosis and help in delineating specific disease subsets, including t(4;14) and 1q21 amplification among others,1, 2, 3, 4, 5 suggesting that these markers may be highly relevant to defining specific patterns of progression and clonal response to therapy.

The pivotal NGS study of MM centered on the MM Research Consortium (MMRC) analysis of 38 tumor genomes that identified key somatic mutations, either at disease presentation or at relapse, but not in a paired setting.6 Consequently, the data did not permit identification of molecular changes under therapy in individual patients longitudinally. Subsequent NGS data described further genomic lesions in MM that are associated with defined chromosomal translocations, including t(4;14), and defined subclonal evolution,7 but again only at disease presentation. Importantly, no single gene mutation or combination of mutations has emerged as universal to all MMs at presentation, across tumor subsets, suggesting that multiple molecular pathways will most likely be responsible for the pathogenesis of this disease and further suggesting that clonal changes under therapy are likely to vary between disease subsets in MM, to be mapped fully.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Chesi M, Bergsagel PL . Many multiple myelomas: making more of the molecular mayhem. Hematology Am Soc Hematol Educ Program 2011; 2011: 344–353.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Klein U, Jauch A, Hielscher T, Hillengrass J, Raab MS, Seckinger A et al. Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone. Cancer 2011; 117: 2136–2144.

    Article  CAS  PubMed  Google Scholar 

  5. Kumar SK, Mikhael JR, Buadi FK, Dingli D, Fonseca R, Gertz MA et al. Management of newly diagnosed symptomatic multiple myeloma: updated mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clinic Proc 2009; 84: 1095–1110.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Al-Lazikani B, Banerji U, Workman P . Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol 2012; 30: 679–692.

    Article  CAS  PubMed  Google Scholar 

  11. Fuentes Fajardo KV, Adams D, Mason CE, Sincan M, Tifft C, NISC Comparative Sequencing Program. Detecting false-positive signals in exome sequencing. Hum Mutat 2012; 33: 609–613.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by EU FP7 Program Project 278706 ‘OVER-MyR’, Leukemia & Lymphoma Research (UK) and Cancer Research UK (JG).

Author information

Author notes

  1. N Weston-Bell and J Gibson: Joint first authors in this study.

  2. A Collins, N Zojer and S S Sahota: Joint senior authors in this study.

Authors and Affiliations

  1. Tumour Immunogenetics Group, Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK

    N Weston-Bell & S S Sahota

  2. Genetic Epidemiology and Genomic Informatics Group, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK

    J Gibson, S Ennis & A Collins

  3. Department of Preclinical Sciences, Faculty of Medical Sciences, University of The West Indies, Trinidad and Tobago

    M John

  4. First Department of Medicine, Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria

    S Pfeifer, H Ludwig & N Zojer

  5. The GenePool, Ashworth Laboratories, University of Edinburgh, Edinburgh, UK

    T Cezard

Authors
  1. N Weston-Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M John
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Ennis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Pfeifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Cezard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N Zojer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S S Sahota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S S Sahota.

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

Reprints and permissions

About this article

Cite this article

Weston-Bell, N., Gibson, J., John, M. et al. Exome sequencing in tracking clonal evolution in multiple myeloma following therapy. Leukemia 27, 1188–1191 (2013). https://doi.org/10.1038/leu.2012.287

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.287

This article is cited by

Search

Advanced search

Quick links