Accessing Genetic Information with Liquid Biopsies

doi:10.1016/j.tig.2015.06.001

Trends in Genetics

Volume 31, Issue 10, October 2015, Pages 564-575

https://doi.org/10.1016/j.tig.2015.06.001 Get rights and content

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There will be huge efforts from both academia and industry to develop ultrasensitive and specific methods, including technology platforms, assays, and data analysis tools for (i) circulating cell isolation, manipulation and characterization/analysis, and (ii) circulating nucleic acids analysis.

There will be large-scale, well-designed clinical trials to demonstrate the clinical utility of ctDNA/CTC for disease detection and monitoring.

There will be continued efforts to integrate knowledge from liquid biopsies into our understanding of health and disease conditions.

Non-invasive, liquid biopsy-based diagnostics will be rapidly incorporated into standard healthcare practice and become the central piece in the future precision medicine.

Recent scientific advances in understanding circulating tumor cells, cell-free DNA/RNA, and exosomes in blood have laid a solid foundation for the development of routine molecular ‘liquid biopsies’. This approach provides non-invasive access to genetic information – somatic mutations, epigenetic changes, and differential expression – about the physiological conditions of our body and diseases. It opens a valuable avenue for future genetic studies and human disease diagnosis, including prenatal and neurodegenerative disease diagnosis, as well as for cancer screening and monitoring. With the rapid development of highly sensitive and accurate technologies such as next-generation sequencing, molecular ‘liquid biopsies’ will quickly become a central piece in the future of precision medicine.

Section snippets

Blood-Based Sources for Future Molecular Diagnosis

Human blood contains rich genetic information which can greatly facilitate accurate diagnosis of a variety of diseases. Genomic DNA derived from leukocytes has long been used as the gold standard for molecular diagnosis of germline genetic diseases. However, there are additional forms of genetic material, albeit in extremely low quantities, within the blood, including DNA/RNA derived from circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs: cfDNA/cfRNA/circulating miRNA) (Box 1) 1

Technologies and Approaches to Analyze CTCs and cfNAs

Several types of genetic information, including somatic mutations, epigenetic modifications, and mRNA/miRNA differential expression, are currently being pursued as biomarkers for cancer and prenatal diagnosis. In particular, cancer-specific somatic mutations have received the most attention.

Concluding Remarks and Future Perspectives

In combination with NGS, liquid biopsies are quickly moving into the clinic, creating a new sphere of molecular diagnostics in areas including prenatal health, oncology, organ transplantation, and neurodegenerative disease 1, 18, 29, 56, 57. Reflective of its rapid development and tremendous potential impact, it was recently selected as one of the top 10 technology breakthroughs in 2015 by MIT Technology Review.

NIPT is the first and, arguably, most-successful clinical adoption of the liquid

Glossary

Companion diagnostics: in vitro diagnostics that provide information essential for the safe and effective use of a corresponding drug or biological product, such as cancer-targeted therapy drugs.
CpG island: in eukaryotic genomes, regions of several hundred bp that are enriched with CpG dinucleotides. They often overlap with transcription start-sites and can regulate gene expression via their differential methylation states [67].
DNA methylation: addition of a methyl group to cytosine residues at the

References (70)

H. Shen et al.
Interplay between the cancer genome and epigenome
Cell
(2013)
J.S. You et al.
Cancer genetics and epigenetics: two sides of the same coin?
Cancer Cell
(2012)
M. Bibikova
High density DNA methylation array with single CpG site resolution
Genomics
(2011)
E.L. van Dijk
Ten years of next-generation sequencing technology
Trends Genet.
(2014)
L.A. Diaz et al.
Liquid biopsies: genotyping circulating tumor DNA
J. Clin. Oncol.
(2014)
D.A. Haber et al.
Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA
Cancer Discov.
(2014)
E. Heitzer
Circulating tumor cells and DNA as liquid biopsies
Genome Med.
(2013)
F-C. Bidard
Going with the flow: from circulating tumor cells to DNA
Sci. Transl. Med.
(2013)
H. Schwarzenbach
Cell-free nucleic acids as biomarkers in cancer patients
Nat. Rev. Cancer
(2011)
F.S. Collins et al.
A new initiative on precision medicine
N. Engl. J. Med.
(2015)

E.S. Lander

Cutting the Gordian helix – regulating genomic testing in the era of precision medicine

N. Engl. J. Med.

(2015)

S. Riethdorf

Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system

Clin. Cancer Res.

(2007)

B. Rack

Circulating tumor cells predict survival in early average-to-high risk breast cancer patients

J. Natl. Cancer Inst.

(2014)

F-C. Bidard

Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data

Lancet Oncol.

(2015)

H.I. Scher

Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer

J. Clin. Oncol.

(2015)

C.L. Hodgkinson

Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer

Nat. Med.

(2014)

M. Yu

Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition

Science

(2013)

N. Aceto

Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis

Cell

(2015)

M. Yu

Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility

Science

(2014)

I. Baccelli

Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay

Nat. Biotechnol.

(2013)

A.F. Sarioglu

A microfluidic device for label-free, physical capture of circulating tumor cell clusters

Nat. Methods

(2015)

P. Benn

Non-invasive prenatal testing for aneuploidy: current status and future prospects

Ultrasound Obstet. Gynecol.

(2013)

A.M. Newman

An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage

Nat. Med.

(2014)

M. Murtaza

Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA

Nature

(2013)

S-J. Dawson

Analysis of circulating tumor DNA to monitor metastatic breast cancer

N. Engl. J. Med.

(2013)

T. Forshew

Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA

Sci. Transl. Med.

(2012)

D.M. Hyman

Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders

Cancer Discov.

(2015)

R. Board

Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer

Breast Cancer Res. Treat.

(2010)

C. Bettegowda

Detection of circulating tumor DNA in early- and late-stage human malignancies

Sci. Transl. Med.

(2014)

K.C.A. Chan

Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing

Proc. Natl. Acad. Sci. U.S.A.

(2013)

J. Skog

Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers

Nat. Cell Biol.

(2008)

F. Properzi

Exosomes: the future of biomarkers in medicine

Biomark. Med.

(2013)

L. Cheng

Prognostic serum miRNA biomarkers associated with Alzheimer

Mol. Psychiatry

(2014)

W. Koh

Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

Proc. Natl. Acad. Sci. U.S.A.

(2014)

Katoh, M. (2014) Cardio-miRNAs and onco-miRNAs: circulating miRNA-based diagnostics for non-cancerous and cancerous...

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^*: Present Address: AnchorDx Corp., Guangzhou 510300, PR China

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Trends in Genetics

ReviewSpecial Issue: Human GeneticsAccessing Genetic Information with Liquid Biopsies

Trends

Section snippets

Blood-Based Sources for Future Molecular Diagnosis

Technologies and Approaches to Analyze CTCs and cfNAs

Concluding Remarks and Future Perspectives

Glossary

Cell

Cancer Cell

Genomics

Trends Genet.

Liquid biopsies: genotyping circulating tumor DNA

J. Clin. Oncol.

Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA

Cancer Discov.

Circulating tumor cells and DNA as liquid biopsies

Genome Med.

Going with the flow: from circulating tumor cells to DNA

Sci. Transl. Med.

Cell-free nucleic acids as biomarkers in cancer patients

Nat. Rev. Cancer

A new initiative on precision medicine

N. Engl. J. Med.

Cutting the Gordian helix – regulating genomic testing in the era of precision medicine

N. Engl. J. Med.

Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system

Clin. Cancer Res.

Circulating tumor cells predict survival in early average-to-high risk breast cancer patients

J. Natl. Cancer Inst.

Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data

Lancet Oncol.

Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer

J. Clin. Oncol.

Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer

Nat. Med.

Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition

Science

Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis

Cell

Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility

Science

Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay

Nat. Biotechnol.

A microfluidic device for label-free, physical capture of circulating tumor cell clusters

Nat. Methods

Non-invasive prenatal testing for aneuploidy: current status and future prospects

Ultrasound Obstet. Gynecol.

An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage

Nat. Med.

Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA

Nature

Analysis of circulating tumor DNA to monitor metastatic breast cancer

N. Engl. J. Med.

Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA

Sci. Transl. Med.

Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders

Cancer Discov.

Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer

Breast Cancer Res. Treat.

Detection of circulating tumor DNA in early- and late-stage human malignancies

Sci. Transl. Med.

Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing

Proc. Natl. Acad. Sci. U.S.A.

Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers

Nat. Cell Biol.

Exosomes: the future of biomarkers in medicine

Biomark. Med.

Prognostic serum miRNA biomarkers associated with Alzheimer

Mol. Psychiatry

Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

Proc. Natl. Acad. Sci. U.S.A.

Review
Special Issue: Human Genetics
Accessing Genetic Information with Liquid Biopsies