Liquid Biopsy and Circulating Biomarkers

Liquid biopsy analyzes biomarkers shed into blood and other body fluids — most prominently cell-free and circulating tumor DNA — to obtain molecular information without sampling tissue directly. It applies the amplification, sequencing, and quantification tools of molecular pathology to minute amounts of nucleic acid circulating in plasma.

Definition

Liquid biopsy is the analysis of tumor- or disease-derived molecular material, especially circulating cell-free nucleic acids, sampled from blood or other body fluids rather than from a solid tissue specimen.

Scope

The topic covers the analysis of circulating cell-free DNA and circulating tumor DNA, along with related circulating biomarkers, and the analytical challenge of detecting rare target molecules against a large normal background. It is presented as methodological reference material, not as clinical testing or treatment guidance.

Key concepts

• Cell-free DNA (cfDNA)
• Circulating tumor DNA (ctDNA)
• Plasma sampling and pre-analytical handling
• Rare-allele detection against background
• Tumor fraction and dynamics over time
• Minimally invasive molecular profiling

Mechanisms

Dying cells release short fragments of DNA into the bloodstream, and a fraction of this cell-free DNA in patients with cancer originates from tumor cells and carries tumor-specific mutations (circulating tumor DNA). Liquid biopsy isolates this material from plasma and uses highly sensitive amplification and sequencing methods to detect rare mutant fragments against a large background of normal DNA, and to track their abundance over time as a measure of disease dynamics (Diehl et al., 2008; Heitzer et al., 2015). Because the signal is often a tiny fraction of total cell-free DNA, careful sample handling and error-suppression strategies are central to reliable detection (Wan et al., 2017).

Clinical relevance

Liquid biopsy offers a minimally invasive way to obtain molecular information and to monitor changes over time. This entry describes the analytical principles as a reference; it does not provide guidance on when to use such tests or how to act on their results in individual patient care.

Evidence & guidelines

The field is supported by primary studies demonstrating that circulating mutant DNA reflects tumor dynamics (Diehl et al., 2008) and by reviews surveying circulating-tumor-DNA methodology and applications (Heitzer et al., 2015; Wan et al., 2017; Corcoran & Chabner, 2018). Detailed analytical-validation and reporting recommendations are addressed in professional consensus documents referenced by these reviews.

History

Cell-free DNA in blood was first described in the mid-twentieth century, but its diagnostic potential became practical only as sufficiently sensitive amplification and sequencing methods emerged. Demonstrations that circulating mutant DNA tracks tumor burden (Diehl et al., 2008) catalyzed the modern field, and subsequent reviews charted its maturation toward broader application (Heitzer et al., 2015; Wan et al., 2017; Corcoran & Chabner, 2018).

Key figures

• Frank Diehl
• Nitzan Rosenfeld
• Ellen Heitzer

Seminal works

• diehl-2008
• heitzer-2015
• wan-2017

Frequently asked questions

What is circulating tumor DNA?

It is the portion of cell-free DNA in the blood that originates from tumor cells and carries tumor-specific genetic alterations, allowing tumor molecular features to be examined from a blood sample.

Why is detecting circulating tumor DNA technically demanding?

Tumor-derived fragments are often a very small fraction of the total cell-free DNA, so highly sensitive amplification and sequencing methods, careful sample handling, and error-suppression are needed to detect the rare mutant molecules reliably.