Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma

S. Manier; J. Park; M. Capelletti; M. Bustoros; S. S. Freeman; G. Ha; J. Rhoades; C. J. Liu; D. Huynh; S. C. Reed; G. Gydush; K. Z. Salem; D. Rotem; C. Freymond; A. Yosef; A. Perilla-Glen; L. Garderet; E. M. Van Allen; S. Kumar; J. C. Love; G. Getz; V. A. Adalsteinsson; I. M. Ghobrial

doi:10.1038/s41467-018-04001-5

Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma

S. Manier, J. Park, M. Capelletti, M. Bustoros, S. S. Freeman, G. Ha, J. Rhoades, C. J. Liu, D. Huynh, S. C. Reed, G. Gydush, K. Z. Salem, D. Rotem, C. Freymond, A. Yosef, A. Perilla-Glen, L. Garderet, E. M. Van Allen, S. Kumar, J. C. LoveG. Getz, V. A. Adalsteinsson, I. M. Ghobrial

Hematology

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

Abstract

Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (∼99%) and copy number alterations (∼81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.

Original language	English (US)
Article number	1691
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04001-5
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-018-04001-5

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Manier, S., Park, J., Capelletti, M., Bustoros, M., Freeman, S. S., Ha, G., Rhoades, J., Liu, C. J., Huynh, D., Reed, S. C., Gydush, G., Salem, K. Z., Rotem, D., Freymond, C., Yosef, A., Perilla-Glen, A., Garderet, L., Van Allen, E. M., Kumar, S., ... Ghobrial, I. M. (2018). Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. Nature communications, 9(1), [1691]. https://doi.org/10.1038/s41467-018-04001-5

Manier, S, Park, J, Capelletti, M, Bustoros, M, Freeman, SS, Ha, G, Rhoades, J, Liu, CJ, Huynh, D, Reed, SC, Gydush, G, Salem, KZ, Rotem, D, Freymond, C, Yosef, A, Perilla-Glen, A, Garderet, L, Van Allen, EM, Kumar, S, Love, JC, Getz, G, Adalsteinsson, VA & Ghobrial, IM 2018, 'Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma', Nature communications, vol. 9, no. 1, 1691. https://doi.org/10.1038/s41467-018-04001-5

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title = "Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma",

abstract = "Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (∼99%) and copy number alterations (∼81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.",

author = "S. Manier and J. Park and M. Capelletti and M. Bustoros and Freeman, {S. S.} and G. Ha and J. Rhoades and Liu, {C. J.} and D. Huynh and Reed, {S. C.} and G. Gydush and Salem, {K. Z.} and D. Rotem and C. Freymond and A. Yosef and A. Perilla-Glen and L. Garderet and {Van Allen}, {E. M.} and S. Kumar and Love, {J. C.} and G. Getz and Adalsteinsson, {V. A.} and Ghobrial, {I. M.}",

note = "Funding Information: We would like to first and foremost acknowledge the courageous patients and their families for participation and contribution to this study. We are also grateful for all the members of Van Allen lab for their helpful discussions and feedback. We thank Tiana Issa for her graphic support. This work was supported in part by NCI R01 CA181683-01A1, the Multiple Myeloma Research Foundation (MMRF), and the Leukemia & Lymphoma Society (LLS). We would also like to acknowledge the generous support of the Gerstner Family Foundation. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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doi = "10.1038/s41467-018-04001-5",

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AU - Manier, S.

AU - Park, J.

AU - Capelletti, M.

AU - Bustoros, M.

AU - Freeman, S. S.

AU - Ha, G.

AU - Rhoades, J.

AU - Liu, C. J.

AU - Huynh, D.

AU - Reed, S. C.

AU - Gydush, G.

AU - Salem, K. Z.

AU - Rotem, D.

AU - Freymond, C.

AU - Yosef, A.

AU - Perilla-Glen, A.

AU - Garderet, L.

AU - Van Allen, E. M.

AU - Kumar, S.

AU - Love, J. C.

AU - Getz, G.

AU - Adalsteinsson, V. A.

AU - Ghobrial, I. M.

N1 - Funding Information: We would like to first and foremost acknowledge the courageous patients and their families for participation and contribution to this study. We are also grateful for all the members of Van Allen lab for their helpful discussions and feedback. We thank Tiana Issa for her graphic support. This work was supported in part by NCI R01 CA181683-01A1, the Multiple Myeloma Research Foundation (MMRF), and the Leukemia & Lymphoma Society (LLS). We would also like to acknowledge the generous support of the Gerstner Family Foundation. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (∼99%) and copy number alterations (∼81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.

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Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma

Abstract

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