Patient monitoring through liquid biopsies using circulating tumor DNA

Abstract

Tumors release components such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived extracellular vesicles into the circulation. Multiple studies have demonstrated that molecular information about tumors and metastases can be extracted from these factors, which are therefore frequently referred to as "liquid biopsies." Liquid biopsies allow the longitudinal monitoring of tumor genomes non-invasively and may hence ensure that patients receive appropriate treatments that target the molecular features of their disease. Accordingly, the number of studies employing liquid biopsy based assays has been skyrocketing in the last few years. Here, we focus on three important issues, which are of high relevance for monitoring tumor genomes. First, we analyze the relation between the allele frequency of somatic tumor-specific mutations and the tumor fraction within plasma DNA. Second, we ask how well current tumor evolution models correlate with findings in longitudinal liquid biopsy studies. And, finally, as sensitivity is one of the key challenges of mutation detection, we address the challenge of detecting mutations occurring at very low allele frequencies in plasma DNA.

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

“…In the present study, this was exemplified by patient #35153 where some of the emerging somatic alterations, such as loss of PTEN or RB1 and the novel gain of 20q13, which harbors the AURKA gene, have been reported as frequent changes in t-NEPC 50–54 and represent a potential therapeutic target 55 . AR antagonism may induce lineage alterations and thus promote enhanced lineage plasticity 19, 52–54, 56 , as previously reported by us and others 11, 19 . Furthermore, we describe several cases in which genomic alterations evolve with disease progression, but at present it is unclear whether these are associated with response/resistance to abiraterone/enzalutamide.…”

Clinical factors associated with circulating tumor DNA (ctDNA) in primary breast cancer

“…Molecular biomarkers related to drug sensitivity and resistance were detected in blood, suggesting that tumor-derived variations in blood may be more clinically relevant than those that are blood-specific. Although many articles have verified the clinical applicability of tumor-derived variations in diverse tumor types (Abbosh et al, 2017;Esposito et al, 2014;Ulz et al, 2017), our study is the first to confirm the utility of tumor-derived variations in blood using basic sequencing analysis. We predict that additional biological and clinical implications of ctDNA profiling will be revealed in further studies with larger populations.…”

Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin

“…To this end, we think that newer approaches such as assay for transposase-accessible chromatin using sequencing (ATAC-seq) (Buenrostro et al 2013) may provide open chromatin data that could be used by our approach. On the other hand, Ulz et al (2017) demonstrated the potential of plasma DNA coverage pattern analysis in inferring the expression of genes thus revealing the tissue origin of tumors in cancer patients. However, the authors estimated that a 75% tumor DNA fraction in the plasma might be required for this purpose (Ulz et al 2017), which was unlikely to be seen in most clinical cases.…”

“…On the other hand, Ulz et al (2017) demonstrated the potential of plasma DNA coverage pattern analysis in inferring the expression of genes thus revealing the tissue origin of tumors in cancer patients. However, the authors estimated that a 75% tumor DNA fraction in the plasma might be required for this purpose (Ulz et al 2017), which was unlikely to be seen in most clinical cases. In contrast, our approach could work on cases with a much lower fraction of DNA from the tissue www.genome.org…”