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Multiple myeloma, gammopathies

Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing

Leukemia volume 32, pages 1838–1841 (2018)Cite this article

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Development of drug resistance [1, 2] and clonal evolution [3,4,5] is a major problem in multiple myeloma (MM) but its comprehensive longitudinal genetic characterization has been impractical thus far. We asked if copy number variations (CNV) and somatic mutations can be called robustly across the entire genome or exome, from cell-free DNA (cfDNA) in patients with active disease, and if clonal somatic mutations and CNVs found in the bone marrow (BM) are reliably reproduced by cfDNA. We hypothesized that (i) the subclonal composition of somatic mutations and CNVs differs, indicating that cfDNA and BM MM cells reveal distinct genetic information [6, 7] and (ii) cfDNA can be used to track disease load and clonal evolution of MM, to provide longitudinal genetic information about disease evolution that is not accessible by bone marrow biopsy [8, 9].

To evaluate the concordance of CNVs and mutations between cfDNA and matched BM myeloma, we performed whole-exome sequencing (WES) of cfDNA, BM-derived CD138+CD45− sorted MM cells and CD138–CD45+ white blood cells as matched normal control from 10 patients to a median depth of 142× (range, 97–250×), 57× (11–137×) and 53× (34–80×), respectively (Supplementary Figure 1 and Supplementary Table 2). In an index patient (R13) with high cfDNA tumor fraction, CNVs were highly concordant between lpWGS of cfDNA, WES of cfDNA, and WES of BM (Fig. 1B and Supplementary Figure 2). High concordance of CNVs was also seen between cfDNA and BM samples of nine other MM patients, even when compared between lpWGS and WES. On average, 90.5% of all CNV segments in BM were concordant with cfDNA, whereas 9.5% were discordant (Supplementary Figure 3).

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Fig. 1
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Author notes

  1. These authors contributed equally: Guangwu Guo, Noopur S Raje.

  2. These authors jointly supervised this work: Jens G. Lohr, Birgit Knoechel.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Guangwu Guo, Charles Seifer, Jake Kloeber, Randi Isenhart, Gavin Ha, Yu-Tzu Tai, Paul G. Richardson, Giada Bianchi, Jacob P. Laubach, Diane Warren, Jordan Voisine, Julia Frede, Antonis Kokkalis, Huiyoung Yun, Valeriya Dimitrova, Tushara Vijaykumar, Matthew Meyerson, Nikhil C. Munshi, Kenneth C. Anderson & Jens G. Lohr

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Guangwu Guo, Charles Seifer, Jake Kloeber, Randi Isenhart, Jordan Voisine, Julia Frede, Antonis Kokkalis, Huiyoung Yun, Valeriya Dimitrova, Tushara Vijaykumar, Birgit Knoechel & Jens G. Lohr

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Guangwu Guo, Charles Seifer, Jake Kloeber, Randi Isenhart, Gavin Ha, Jordan Voisine, Julia Frede, Antonis Kokkalis, Huiyoung Yun, Valeriya Dimitrova, Tushara Vijaykumar, Matthew Meyerson, Birgit Knoechel & Jens G. Lohr

  4. Harvard Medical School, Boston, MA, USA

    Noopur S. Raje, Andrew J. Yee, Elizabeth K. O’Donnell, Yu-Tzu Tai, Paul G. Richardson, Giada Bianchi, Jacob P. Laubach, Diane Warren, Matthew Meyerson, Nikhil C. Munshi, Kenneth C. Anderson, Birgit Knoechel & Jens G. Lohr

  5. Center for Multiple Myeloma, Massachusetts General Hospital, Boston, MA, USA

    Noopur S. Raje, Andrew J. Yee, Elizabeth K. O’Donnell & Erica Gemme

  6. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA

    Matthew Meyerson

  7. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Matthew Meyerson

  8. Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, USA

    Paul G. Richardson, Giada Bianchi, Jacob P. Laubach, Nikhil C. Munshi & Kenneth C. Anderson

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  1. Guangwu Guo
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Correspondence to Jens G. Lohr.

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MM is a founder and consultant to Foundation Medicine, Inc., a provider of cancer genome-based diagnostic testing.

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Guo, G., Raje, N.S., Seifer, C. et al. Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing. Leukemia 32, 1838–1841 (2018). https://doi.org/10.1038/s41375-018-0115-z

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