Liquid Biopsies beyond Mutation Calling: Genomic and Epigenomic Features of Cell-Free DNA in Cancer

Abstract

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.

Serum cytokines predict efficacy and toxicity, but are not useful for disease monitoring in lung cancer treated with PD-(L)1 inhibitors

“…Therefore, the results will need to be validated in future studies, which might pave the way for building a complex score based on several cytokines and data mining analysis ( 59 ). Other emerging approaches to refine patient stratification are measurement of circulating tumor cells, ctDNA, miRNA, blood exosomes, gene expression profiling, or analysis of the T-cell receptor (TCR) repertoire ( 18 , 37 , 60 – 64 ).…”

Circulating tumor nucleic acids: biology, release mechanisms, and clinical relevance

“…DNA released by tumor cells may possess alterations that can provide highly specific markers for detection [ 6 , 8 , 11 ]. Notably, compared to healthy individuals, cancer patients’ blood has been observed to contain increased levels of cfDNA [ 12 ] as well as messenger RNA (mRNA) and non-coding RNA (ncRNA) [ 13 , 14 ]. Cell-free nucleic acids (cfNAs) can be released passively into circulation mainly via apoptosis and necrosis as well as through active secretion via extracellular vesicles (EVs) from viable cells.…”

Brief Report: A Blood-Based MicroRNA Complementary Diagnostic Predicts Immunotherapy Efficacy in Advanced-Stage NSCLC With High Programmed Death-Ligand 1 Expression

“…There is great interest in the discovery of blood-based biomarkers that are predictive of immunotherapy response due to their ease of noninvasive collection and their potential to capture signal both from the peripheral immune system and material shed from the tumor itself. 16 Efforts to measure soluble PD-L1 status 17 and plasma tumor mutational burden 18 were found to be promising; however, these are yet to be approved for clinical use. Immune cell RNA profiling and next-generation sequencing-based methods could enable improved prediction with additional integration of signal from multiple sources, such as peripheral effector cell counts.…”