Genetic interrogation of circulating multiple myeloma cells at single-cell resolution.
Multiple myeloma (MM) remains an incurable disease, with a treatment-refractory state eventually developing in all patients. Constant clonal evolution and genetic heterogeneity of MM are a likely explanation for the emergence of drug-resistant disease. Monitoring of MM genomic evolution on therapy by serial bone marrow biopsy is unfortunately impractical because it involves an invasive and painful procedure. We describe how noninvasive and highly sensitive isolation and characterization of circulating tumor cells (CTCs) from peripheral blood at single-cell resolution recapitulate MM in the bone marrow. We demonstrate that CTCs provide the same genetic information as bone marrow MM cells and even reveal mutations with greater sensitivity than bone marrow biopsies in some cases. Single CTC RNA sequencing enables classification of MM and quantitative assessment of genes that are relevant for prognosis. We propose that the genomic characterization of CTCs should be included in clinical trials to follow the emergence of resistant subclones after MM therapy.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. golub@broadinstitute.org jlohr@partners.org.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.|Harvard Medical School, Boston, MA 02115, USA.
Jens G
JG
Lohr
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Sora
S
Kim
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Joshua
J
Gould
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.|Harvard Medical School, Boston, MA 02115, USA.
Birgit
B
Knoechel
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Harvard Medical School, Boston, MA 02115, USA.|Division of Hematology and Oncology/Pathology, Massachusetts General Hospital Cancer Center, MA 02114, USA.
Yotam
Y
Drier
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Hematology and Oncology/Pathology, Massachusetts General Hospital Cancer Center, MA 02114, USA.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Matthew J
MJ
Cotton
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Daniel
D
Gray
Division of Hematology and Oncology/Pathology, Massachusetts General Hospital Cancer Center, MA 02114, USA.
Nicole
N
Birrer
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Bang
B
Wong
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.
Gavin
G
Ha
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.
Cheng-Zhong
CZ
Zhang
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.|Harvard Medical School, Boston, MA 02115, USA.
Guangwu
G
Guo
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.|Harvard Medical School, Boston, MA 02115, USA.
Matthew
M
Meyerson
Harvard Medical School, Boston, MA 02115, USA.|Division of Hematology and Oncology/Pathology, Massachusetts General Hospital Cancer Center, MA 02114, USA.
Andrew J
AJ
Yee
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jesse S
JS
Boehm
Harvard Medical School, Boston, MA 02115, USA.|Division of Hematology and Oncology/Pathology, Massachusetts General Hospital Cancer Center, MA 02114, USA.
Noopur
N
Raje
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. golub@broadinstitute.org jlohr@partners.org.|Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02214, USA.|Harvard Medical School, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Todd R
TR
Golub
D001853:Bone Marrow / Q000473:pathology*; D004252:DNA Mutational Analysis; D005240:Feasibility Studies; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D009101:Multiple Myeloma / Q000097:blood / Q000235:genetics*; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D010950:Plasma Cells / Q000378:metabolism; D011379:Prognosis; D000075082:Proof of Concept Study; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D014158:Transcription, Genetic; D047368:Tumor Burden