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Current and future perspectives of liquid biopsies in genomics-driven oncology

Nature Reviews Genetics volume 20, pages 71–88 (2019)Cite this article

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Abstract

Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sampling frequency and their incomplete representation of the entire tumour bulk. Now, attention is turning to minimally invasive liquid biopsies, which enable analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence. However, the analytical validity and clinical utility of liquid biopsies must be rigorously demonstrated before this potential can be realized.

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Fig. 1: Factors influencing the sensitivity of a plasma cell-free DNA test.
Fig. 2: The amount of input cell-free DNA affects the ability to detect rare variants.
Fig. 3: Determining the tissue of origin of nucleic acids in plasma.
Fig. 4: Combination strategies for early detection of cancer from liquid biopsy samples.

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Acknowledgements

The authors thank P. Ulz for his assistance in drafting the figures for this article and S. Perakis for her assistance in revising the text. The work in the authors’ laboratory is supported by CANCER-ID, a project funded by the Innovative Medicines Joint Undertaking; the Austrian National Bank (grant 16917); the Austrian Science Fund (grant P28949-B28); the BioTechMed-Graz flagship project ‘EPIAge’; and the Christian Doppler Research Fund for Liquid Biopsies for Early Detection of Cancer.

Reviewer information

Nature Reviews Genetics thanks P. Hofman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria

    Ellen Heitzer & Michael R. Speicher

  2. BioTechMed-Graz, Graz, Austria

    Ellen Heitzer & Michael R. Speicher

  3. Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, Graz, Austria

    Ellen Heitzer

  4. Freenome, South San Francisco, CA, USA

    Imran S. Haque & Charles E. S. Roberts

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  1. Ellen Heitzer
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Contributions

E.H. and M.R.S. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission. I.S.H. and C.E.S.R. wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Ellen Heitzer.

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I.S.H. and C.E.S.R. are employees of Freenome. Freenome is the industrial partner of the Christian Doppler Research Fund for Liquid Biopsies for Early Detection of Cancer, which is headed by E.H. The authors declare that no other competing interests exist.

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Related links

BloodPAC: www.bloodpac.org

Blueprint Epigenome consortium: www.blueprint-epigenome.eu/

Cancer-ID: www.cancer-id.eu

CEN/TS 16835-3:2015: https://standards.cen.eu/dyn/www/f?p=204:110:0::::FSP_PROJECT:41040&cs=171988FF551BF281CD5E65F5D59C82961

International Human Epigenome Consortium (IHEC): http://ihec-epigenomes.org/

Standardization of generic pre-analytical procedures for in vitro diagnostics for personalized medicine (SPIDIA4P): http://www.spidia.eu/about-the-projects/

The European Committee for Standardization (CEN): https://standards.cen.eu

Glossary

Precision oncology

Molecular profiling of a tumour with the aim to detect somatic alterations that can be targeted for therapy.

Next-generation sequencing

(NGS). A high-throughput method used to determine the nucleotide sequence of DNA or RNA.

The Cancer Genome Atlas

(TCGA). A comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies.

Epigenetic

A biochemical change in the genome, such as DNA methylation or histone modification, that does not alter the DNA sequence but may affect gene activity and expression.

Druggable targets

Somatic mutations involved in cancer development and progression that can be exploited with a therapeutic intent.

Pleural effusions

Excessive accumulations of fluid in the space surrounding the lung (pleural cavity).

Circulating tumour cells

(CTCs). Cells that have been shed into the vasculature or lymphatics from a primary tumour and/or metastasis and are carried around the body in the blood circulation.

Circulating cell-free DNA

(cfDNA). DNA circulating in the bloodstream that is not associated with cells.

Circulating tumour DNA

(ctDNA). Tumour-derived, cell-free DNA that is thought to be representative of the entire tumour genome.

Circulating cell-free RNA

(cfRNA). Circulating gene transcripts (mRNA and non-coding RNAs) that are partly protected from degradation by their packaging into exosomes.

Extracellular vesicles

(EVs). Generic term for vesicles, including exosomes, microvesicles or apoptotic bodies, that are secreted from all cells and carry complex cargoes such as proteins, lipids and nucleic acids across biological membranes.

Exosomes

Cell-derived vesicles likely present in all body fluids, which contain nucleic acids, lipids and metabolites and are involved in intercellular signalling and communication.

Tumour-educated platelets

(TEPs). Platelets with altered functions that interact with tumour cells via different signalling molecules, thereby promoting tumour cell survival and metastasis.

Copy number alterations

Loss (deletion) or gain (ranging from duplication to high-level amplification) of genomic regions resulting in a copy number that deviates from two.

Transcriptome

The full range of mRNA molecules expressed in a cell, tissue or organism at a certain time.

Epigenome

The full complement of epigenetic marks within a genome, which helps to determine the activity of genes in any particular cell and its lineage. The epigenome is prone to change during ageing and in cancer cells.

Proteome

The entire set of proteins expressed in a cell, tissue or organism at a certain time.

Metabolome

The complete set of small-molecule chemicals found within a cell, tissue or organism at a certain time.

Laboratory-developed tests

(LDTs). According to US Food and Drug Administration regulations, these tests are in vitro diagnostic tests designed, manufactured and used within a single laboratory.

Epithelial cell adhesion molecules

(EpCAMs). Transmembrane glycoproteins that are expressed solely in epithelia and epithelial-derived cancer and are commonly used as a diagnostic marker.

Variant allele frequency

(VAF). The frequency of a particular allele of a gene relative to all other alleles in a DNA sample.

Metabolic tumour volume

The proportion of a tumour, measured by volume, that is hypermetabolic. Often measured by positron emission tomography.

Minimal residual disease

Cancer cells that remain in the patient’s body during and after treatment, frequently escape detection by routine diagnostic procedures and are critically involved in relapse.

Genome equivalents

(GE). The amount of DNA that corresponds to the diploid genome of a single cell.

Sequencing sensitivity

The analytical sensitivity of a sequencing method; that is, the ability to detect a low concentration of a particular sequence in a biological sample. The sequencing sensitivity of an approach determines its ability to accurately measure the variant allele frequency of a variant.

Molecular barcodes

Degenerate sequence tags consisting of random or specified bases to label DNA fragments in order to track individual molecules after PCR; they are also referred to as unique molecular identifiers.

Cancer driver gene

A gene that, when mutated, is essential for cancer to develop and progress and that is under positive selection during tumour evolution.

Clonal expansion

A process in which acquisition of somatic mutations drives the production of daughter cells all arising from a single cell.

Methylomes

All nucleic acid methylation modifications in the genomes of cells.

Bisulfite sequencing

A method for detecting DNA methylation patterns. DNA is treated with bisulfite, which converts cytosine but not 5-methylcytosine to uracil, enabling methylated and unmethylated cytosines to be discriminated from sequencing data.

Classifier

A means to group data into categories on the basis of certain characteristics, such as inherent similarity.

Tumour mutational burden

(TMB). A biomarker that measures the number of mutations present in a tumour of a patient with cancer. Usually, given as the number of coding somatic mutations per megabase of DNA.

Diagnostic sensitivity

The likelihood that a diagnostic test will be positive when testing a person with the disease.

Diagnostic specificity

The likelihood that a diagnostic test will be negative when testing a person without the disease.

Positive predictive value

(PPV). The proportion of positive results in diagnostic tests. PPV depends on the sensitivity and specificity of the test and on the prevalence of the disease within the general population.

Deconvolution

The process of extracting cell type-specific information from heterogeneous samples. In liquid biopsies, this might involve resolving plasma DNA fragments into their constituent elements (for example, determining their tissue of origin on the basis of methylation markers).

Hidden layers

The intermediate layers of information generated when an artificial neural network breaks down and processes input data to generate the output.

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Heitzer, E., Haque, I.S., Roberts, C.E.S. et al. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 20, 71–88 (2019). https://doi.org/10.1038/s41576-018-0071-5

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