American Association for Cancer Research
cd-22-0482_supplementary_figures_and_tables_suppsd1.pdf (2.41 MB)

Supplementary Figures and Tables from MinimuMM-seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

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journal contribution
posted on 2023-11-08, 13:00 authored by Ankit K. Dutta, Jean-Baptiste Alberge, Elizabeth D. Lightbody, Cody J. Boehner, Andrew Dunford, Romanos Sklavenitis-Pistofidis, Tarek H. Mouhieddine, Annie N. Cowan, Nang Kham Su, Erica M. Horowitz, Hadley Barr, Laura Hevenor, Jenna B. Beckwith, Jacqueline Perry, Amanda Cao, Ziao Lin, Frank K. Kuhr, Richard G. Del Mastro, Omar Nadeem, Patricia T. Greipp, Chip Stewart, Daniel Auclair, Gad Getz, Irene M. Ghobrial

Supplementary data contains additional Materials and Methods used to generate results presented only in the supplementary figures and tables, as well as more detailed bioinformatics methods. Figure S1 shows correlation between clinical measures of disease pathology, survival, and circulating tumor cells enumeration. Figure S2 shows characteristics of isolated circulating tumor cells from peripheral blood of precursor disease patients. Figure S3 shows cohort-level genomic characterization of tumor in MM precursor stages with CTCs. Figure S4 shows longitudinal and tissue-matched genomic characterization of driver mutations. Figure S5 shows comparison of mutational processes between BMPCs and CTCs assigned to most likely PCAWG composite reference signature. Table S1 shows clinical characteristics and sampling of participants in this study. Table S2 shows whole-genome sequencing coverage and library metrics. Table S3 shows clinical BM FISH results and cells recovered for cohort with matched samples. Table S4 shows comparison of BCR sequence between BMPCs and CTCs. Table S5 shows clinical BM FISH results of peripheral blood only cohort and CTCs recovered. Table S6 shows enumeration of single nucleotide variants and short insertions and deletions discovered from WGS of CTCs. Table S7 shows enumeration of structural variants reconstructed from WGS of CTCs.


National Institutes of Health (NIH)

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)

International Myeloma Society (IMS)

Stand Up To Cancer (SU2C)



Multiple myeloma (MM) develops from well-defined precursor stages; however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. We enumerated circulating tumor cells (CTC) from 261 patients (84 monoclonal gammopathy of undetermined significance, 155 smoldering multiple myeloma, and 22 MM), with neoplastic cells detected in 84%. We developed a novel approach, MinimuMM-seq, which enables the detection of translocations and copy-number abnormalities through whole-genome sequencing of highly pure CTCs. Application to CTCs in a cohort of 51 patients, 24 with paired BM, was able to detect 100% of clinically reported BM biopsy events and could replace molecular cytogenetics for diagnostic yield and risk classification. Longitudinal sampling of CTCs in 8 patients revealed major clones could be tracked in the blood, with clonal evolution and shifting dynamics of subclones over time. Our findings provide proof of concept that CTC detection and genomic profiling could be used clinically for monitoring and managing disease in MM. In this study, we established an approach enabling the enumeration and sequencing of CTCs to replace standard molecular cytogenetics. CTCs harbored the same pathognomonic MM abnormalities as BM plasma cells. Longitudinal sampling of serial CTCs was able to track clonal dynamics over time and detect the emergence of high-risk genetic subclones.This article is highlighted in the In This Issue feature, p. 247

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