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. 2017 Apr 4;19(1):218-224.
doi: 10.1016/j.celrep.2017.03.025.

The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma

Yuji Mishima  1 , Bruno Paiva  2 , Jiantao Shi  3 , Jihye Park  4 , Salomon Manier  5 , Satoshi Takagi  5 , Mira Massoud  5 , Adriana Perilla-Glen  5 , Yosra Aljawai  5 , Daisy Huynh  5 , Aldo M Roccaro  6 , Antonio Sacco  6 , Marzia Capelletti  5 , Alexandre Detappe  5 , Diego Alignani  2 , Kenneth C Anderson  5 , Nikhil C Munshi  5 , Felipe Prosper  2 , Jens G Lohr  7 , Gavin Ha  7 , Samuel S Freeman  7 , Eliezer M Van Allen  4 , Viktor A Adalsteinsson  7 , Franziska Michor  3 , Jesus F San Miguel  2 , Irene M Ghobrial  8
Affiliations

The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma

Yuji Mishima et al. Cell Rep. .

Abstract

The development of sensitive and non-invasive "liquid biopsies" presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.

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Figures

Figure 1
Figure 1. Concordance of SSNVs Found in Matched BM Clonal PCs and CTCs
(A) Rate of synonymous and nonsynonymous mutations are expressed in number of mutations per megabase. Heatmap representation of individual mutations is present in a series of eight paired BM and CTC samples. Breakdown of individual base-substitution rates is shown for each sample as well. (B) Heatmap representation of individual mutations is present in 13 WES CTC samples and 16 targeted sequencing CTC samples. Percentages represent the fraction of tumors harboring at least one mutation in specified genes.
Figure 2
Figure 2. Clustering Analysis of Clonal and Subclonal SSNVs between Matched BM Clonal PCs and CTCs
Clustering analysis of CCF for SSNVs between matched BM clonal PCs and CTCs is shown in this figure. Shared clonal SSNVs were defined as events having ≥0.9 CCF in both samples (red). Shared subclonal SSNVs were identified as events having ≥0.05 CCF in both samples (blue). Not shared subclonal SSNVs were defined as events having <0.05 CCF in either BM or CTC samples (green). The size of each cluster indicates the frequency of SSNVs within the same sample.
Figure 3
Figure 3. Concordance of Somatic Copy-Number Alterations Found in Matched BM Clonal PCs and CTCs
Arm level of somatic copy-number alterations are compared within the same patient (left, BM; right, CTC). Red indicates amplification, and blue indicates deletion.
Figure 4
Figure 4. Representative Example of Somatic Copy-Number Alterations Found in Matched BM Clonal PCs and CTCs
Allelic copy number ratios are shown for both BM (top) and CTC (bottom) samples within the same patient (434 and 453, respectively).
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