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.

Clinical utility of circulating tumor DNA for colorectal cancer

“…To overcome this limitation, it is essential to develop highly sensitive and reproducible detection methods to identify ctDNA. Methodologies for detecting ctDNA are shown in Table …”

“…Methodologies for detecting ctDNA are shown in Table 2. [35][36][37][38][39][40][41][42][43][44][45] Digital droplet PCR uses a droplet generator to partition single pieces of DNA into droplets using an oil/water emulsion. 46 Each molecule is individually analyzed for target sequences through an end-point PCR, allowing the detection of mutant or wild-type DNA fragments.…”

Dynamics of tumor‐specific cfDNA in response to therapy in multiple myeloma patients

“…It provides non‐ or minimally invasive alternative to diagnosis, treatment monitoring and MRD monitoring from body fluids . One of the most promising target molecules in liquid biopsies are cell‐free DNA (cfDNA), short double‐stranded DNA molecules circulating in various body fluids . Low levels of these molecules can be found even in healthy individuals; however, levels of cfDNA were found to be considerably elevated in various pathological conditions .…”

Assessment of circulating tumor DNA in pediatric solid tumors: The promise of liquid biopsies

“…There are numerous technology‐specific and context‐specific considerations that must be evaluated when choosing an approach for the detection of ctDNA. We have summarized what we consider to be the most important and commonly encountered considerations in Table …”