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

Manier S1,2,3, Park J1,4, Capelletti M1, Bustoros M1, Freeman SS5, Ha G5, Rhoades J5, Liu CJ1, Huynh D1, Reed SC5, Gydush G5, Salem KZ1, Rotem D5, Freymond C1, Yosef A1, Perilla-Glen A1, Garderet L6, Van Allen EM1,5, Kumar S7, Love JC5, Getz G5, Adalsteinsson VA8, Ghobrial IM9,10,11.

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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.