Abstract
Simple SummaryLiquid biopsies provide a non-invasive means to diagnose and profile tumors when tissue is not available. Sequence-based analysis of cell-free DNA (cfDNA) is frequently used to characterize genomic alterations, with a focus on driver mutations or mechanisms of acquired therapy resistance. However, the epigenome of cfDNA also contains additional information about the tumor, which might open new possibilities for clinical applications. Recent highlighted publications are reviewed on the analysis of fragmentation, epigenomic alterations, as well as nucleosome modifications using cfDNA in various cancers. The potential, challenges, and future directions of genomic and epigenomic analysis of cfDNA in oncology are discussed.Cell-free DNA (cfDNA) analysis using liquid biopsies is a non-invasive method to gain insights into the biology, therapy response, mechanisms of acquired resistance and therapy escape of various tumors. While it is well established that individual cancer treatment options can be adjusted by panel next-generation sequencing (NGS)-based evaluation of driver mutations in cfDNA, emerging research additionally explores the value of deep characterization of tumor cfDNA genomics and fragmentomics as well as nucleosome modifications (chromatin structure), and methylation patterns (epigenomics) for comprehensive and multi-modal assessment of cfDNA. These tools have the potential to improve disease monitoring, increase the sensitivity of minimal residual disease identification, and detection of cancers at earlier stages. Recent progress in emerging technologies of cfDNA analysis is summarized, the added potential clinical value is highlighted, strengths and limitations are identified and compared with conventional targeted NGS analysis, and current challenges and future directions are discussed.
Highlights
The development of advanced genomic technologies has caused an upsurge in methods of cell-free DNA analysis during the past decade
Healthy tissue) remains a prevailing limitation in genomic analyses of Cell-free DNA (cfDNA). Another limitation is that—while it is possible to track tumor progression based on cfDNA single nucleotide variations (SNVs) and copy number variations (CNVs)—definitive identification of a tumor’s tissue-of-origin based on these parameters is not always possible
Jiang et al [42] demonstrated that the cfDNA fragment length profile in patients suffering from hepatocellular carcinoma (HCC) was shifted towards lower sizes compared with healthy individuals (145 bp)
Summary
The development of advanced genomic technologies has caused an upsurge in methods of cell-free DNA (cfDNA) analysis during the past decade. The detection and quantification of mutations, CNVs, and aneuploidies from tumor-derived cfDNA have been successfully used to monitor advanced disease and treatment response [9–11]. Multiple studies have reported the potential of ctDNA analysis in oligoprogression [14] as well as in early detection of disease progression (i.e., lead time), in which detection of tumor mutational clones precedes conventional imaging modalities [15–18]. Healthy tissue) remains a prevailing limitation in genomic analyses of cfDNA. Another limitation is that—while it is possible to track tumor progression based on cfDNA single nucleotide variations (SNVs) and copy number variations (CNVs)—definitive identification of a tumor’s tissue-of-origin based on these parameters is not always possible. Beyond the conventional cfDNA analysis using targeted NGS (tNGS) [19,20], epigenomic changes in tumor tissues vary during tumor initiation and progression [21]. A major challenge hindering translation into clinical applications is the low abundance of analytes derived from certain tumor types, such as prostate [32], glioblastoma [33], and renal cancers [34], especially in early tumor stages [35]
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