Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides

Jan B. Egan, Chang Xin Shi, Waibhav Tembe, Alexis Christoforides, Ahmet Kurdoglu, Shripad Sinari, Sumit Middha, Yan Asmann, Jessica Schmidt, Esteban Braggio, Jonathan J. Keats, Rafael Fonseca, P. Leif Bergsagel, David W. Craig, John D. Carpten, A. Keith Stewart

Research output: Contribution to journalArticle

288 Scopus citations

Abstract

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) onWGScomprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.

Original languageEnglish (US)
Pages (from-to)1060-1066
Number of pages7
JournalBlood
Volume120
Issue number5
DOIs
StatePublished - Aug 2 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Egan, J. B., Shi, C. X., Tembe, W., Christoforides, A., Kurdoglu, A., Sinari, S., Middha, S., Asmann, Y., Schmidt, J., Braggio, E., Keats, J. J., Fonseca, R., Bergsagel, P. L., Craig, D. W., Carpten, J. D., & Stewart, A. K. (2012). Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood, 120(5), 1060-1066. https://doi.org/10.1182/blood-2012-01-405977