Abstract
SummaryCell-free DNA (cfDNA) measured via liquid biopsies provides a way for minimally invasive monitoring of tumor evolutionary dynamics during therapy. Here we present liquidCNA, a method to track subclonal evolution from longitudinally collected cfDNA samples sequenced through cost-effective low-pass whole-genome sequencing. LiquidCNA utilizes somatic copy number alteration (SCNA) to simultaneously genotype and quantify the size of the dominant subclone without requiring B-allele frequency information, matched-normal samples, or prior knowledge on the genetic identity of the emerging clone. We demonstrate the accuracy of liquidCNA in synthetically generated sample sets and in vitro mixtures of cancer cell lines. In vivo application in patients with metastatic lung cancer reveals the progressive emergence of a novel tumor subpopulation. LiquidCNA is straightforward to use, is computationally inexpensive, and enables continuous monitoring of subclonal evolution to understand and control-therapy-induced resistance.
Highlights
SUMMARY Cell-free DNA measured via liquid biopsies provides a way for minimally invasive monitoring of tumor evolutionary dynamics during therapy
We present liquidCNA, a method to track subclonal evolution from longitudinally collected Cell-free DNA (cfDNA) samples sequenced through cost-effective low-pass wholegenome sequencing
We demonstrate the accuracy of liquidCNA in synthetically generated sample sets and in vitro mixtures of cancer cell lines
Summary
Primarily the analysis of cell-free DNA (cfDNA) present in blood samples, offer the potential for regular longitudinal and minimally invasive monitoring of cancer dynamics (Siravegna et al, 2017; Ng et al, 2017; Rothwell et al, 2019; Khan et al, 2018; Fernandez-Garcia et al, 2019; Conteduca et al, 2020; Nakamura et al, 2020). KRAS mutation frequency in cfDNA is predictive of response to anti-EGFR therapy (Khan et al, 2018)
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