Cell-free DNA promises to transform how we find diseases in advance

Last Updated01/08/2023

In the human body, most of the DNA in a genome is neatly packed inside cells with the help of specific proteins, protecting it from being degraded.
However, in a variety of scenarios,some fragments of DNA are ‘released’ from their containers and are present outside the cell, in body fluids.
These small fragments of nucleic acids are widely known as cell-free DNA (cfDNA).

cfDNA can be generated and released from a cell in a number of possible situations, including when a cell is dying and the nucleic acids become degraded.
Array of processes modulates the degradation, the amount, size, and source of the cfDNA can vary across a range as well.
The release of cfDNA could occur together with a variety of processes, including
- Normal development
- Development of certain cancers
- Several other diseases.
One of the initial reports of the levels of cfDNA in diseases came from studies that were taking a closer look at an autoimmune disease: systemic lupus erythematosus where the body’s own immune system attacks specific cells.

Most widely used applications of cfDNA have been in screening foetuses for specific chromosomal abnormalities, an application known as non-invasive prenatal testing.
The availability of affordable genome-sequencing approaches will allow clinicians to sequence cfDNA fragments that correspond to foetal DNA.
They can then use it to understand specific chromosomal abnormalities that involve changes in the chromosomal copy number.
Such changes can lead to conditions such as Down’s syndrome, which is due to a change in chromosome 21 .
As a result, thanks to a cfDNA-based technique, clinicians can now screen mothers from a few millilitres of blood, obtained after nine or ten weeks of pregnancy, to ensure the developing foetus is devoid of such chromosomal abnormalities.
The test is almost 99% accurate for trisomy 21 or Down’s syndrome and a bit less so for other common trisomies (of chromosomes 13 and 18).
Screening for such abnormalities before the genome-sequencing era would have entailed inserting a fine needle into the body to retrieve the amniotic fluid and cells covering the developing foetus, and analysing them in the lab. This method carries risks to both the foetus and the mother.

Another emerging application of cfDNA is in the early detection, diagnosis, and treatment of cancers.
Last month, researchers reported developing a new test they have dubbed ‘Genome-wide Mutational Incidence for Non-Invasive detection of cancer’, or ‘GEMINI’. They adopted a whole-genome-sequencing approach to cfDNA extracted from patients.
Specifically, the researchers examined a type of genetic mutation that, when combined with machine-learning approaches, could provide a way to detect cancer early.
Using a particular machine-learning model, some genomic data, and data from a computed tomography (CT) scan, the researchers could successfully detect lung cancer.
It has also been found to detect over 300 individuals who were at high risk of developing lung cancer.

There are a number of emerging applications of cfDNA, including in understanding why a body is rejecting a transplanted organ.
Here, some cfDNA obtained from the donor of the organ – called donor-derived cfDNA, dd-cfDNA – could provide an early yet accurate estimate of how well the organ is being taken up.
Indeed, cfDNA seems to have an almost infinite number of applications, especially as nucleic-acid sequencing becomes rapidly democratised and finds more applications of its own in clinical settings.
There have already been some reports suggesting that cfDNA could be used as a biomarker for neurological disorders like Alzheimer’s disease, neuronal tumours, stroke, traumatic brain injury, and even metabolic disorders such as type-2 diabetes and non-alcoholic fatty liver disease.

In a true sense, cfDNA genomics promises to set us on the path of more effective disease-screening and early diagnosis, and of course for a healthy world.