A quick and easy Australian test to detect cancer from blood or biopsy tissue has proved to be up to 90% accurate in tests involving 200 human cancer samples.
The test has been developed by University of Queensland researchers Dr Abu Sina, Dr Laura Carrascosa and Professor Matt Trau, who have discovered a unique DNA nanostructure that appears to be common to all cancers.
Cancer is an extremely complicated and variable disease and different types of cancer have different signatures. Sina said it had been difficult to find a simple signature that was distinct from healthy cells and common to all cancers. “This unique nano-scaled DNA signature appeared in every type of breast cancer we examined, and in other forms of cancer including prostate, colorectal and lymphoma,” he said.
“The levels and patterns of tiny molecules called methyl groups that decorate DNA are altered dramatically by cancer – these methyl groups are key for cells to control which genes are turned on and off.”
Carrascosa said they took a holistic approach and developed a tool that could look at these pattern changes at the whole genome level within minutes. “In healthy cells, these methyl groups are spread out across the genome, but the genomes of cancer cells are essentially barren except for intense clusters of methyl groups at very specific locations.”
Trau said the team discovered that intense clusters of methyl groups placed in a solution caused cancer DNA fragments to fold into unique three-dimensional nanostructures that could easily be separated by sticking to solid surfaces such as gold. “We designed a simple test using gold nanoparticles that instantly change colour to determine if the 3D nanostructures of cancer DNA are present,” Trau said.
He said cancer cells released their DNA into blood plasma when they died. “So we were very excited about an easy way of catching these circulating free cancer DNA signatures in blood,” he said.
“Discovering that cancerous DNA molecules formed entirely different 3D nanostructures from normal circulating DNA was a breakthrough that has enabled an entirely new approach to detect cancer non-invasively in any tissue type including blood.
“This led to the creation of inexpensive and portable detection devices that could eventually be used as a diagnostic tool, possibly with a mobile phone.”
The new technology has proved to be up to 90% accurate in tests involving 200 human cancer samples and normal DNA.
“We certainly don't know yet whether it’s the holy grail for all cancer diagnostics, but it looks really interesting as an incredibly simple universal marker of cancer, and as an accessible and inexpensive technology that doesn’t require complicated lab-based equipment like DNA sequencing,” Trau said.
The research has been supported by a grant from the National Breast Cancer Foundation.
The study included researchers from UQ’s Australian Institute for Bioengineering and Nanotechnology, School of Chemistry and Molecular Biosciences, School of Medicine and Diamantina Institute. Researchers are working with UniQuest, UQ’s commercialisation company, to further develop the technology and licence with a commercial partner.
Abstract
Epigenetic reprogramming in cancer genomes creates a distinct methylation landscape encompassing clustered methylation at regulatory regions separated by large intergenic tracks of hypomethylated regions. This methylation landscape that we referred to as Methylscape is displayed by most cancer types, thus may serve as a universal cancer biomarker. To-date most research has focused on the biological consequences of DNA Methylscape changes whereas its impact on DNA physicochemical properties remains unexplored. Herein, we examine the effect of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to detect the Methylscape biomarker. We find that DNA polymeric behaviour is strongly affected by differential patterning of methylcytosine, leading to fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes. We exploit these Methylscape differences to develop simple, highly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer. These assays are quick, i.e., analysis time ≤10 minutes, and require minimal sample preparation and small DNA input.
Authors
Abu Ali Ibn Sina, Laura G Carrascosa, Ziyu Liang, Yadveer S Grewal, Andri Wardiana, Muhammad JA Shiddiky, Robert A Gardiner, Hemamali Samaratunga, Maher K Gandhi, Rodney J Scott, Darren Korbie, Matt Trau
Sina, Carracosa and Trau discuss their research in an article in The Conversation.
They write: “Our research has found that cancer DNA forms a unique structure when placed in water. The structure is the same in DNA from samples of breast, prostate and bowel cancers, as well as lymphoma. We used this discovery to develop a test that can identify the cancerous DNA in less than ten minutes.
“Current detection of cancer requires a tissue biopsy – a surgical procedure to collect tissue from the patient’s tumour. Researchers have been looking for a less invasive diagnostic test that can detect cancers at an earlier stage. One possibility, still in development, is a liquid biopsy, testing for circulating cancer DNA in the blood.
“Our test also uses circulating cancer DNA but involves a different detection method.
“Nearly every cell in a person’s body has the same DNA, but studies have found that cancer’s progression causes this DNA to undergo considerable reprogramming.
“This change is particularly evident in the distribution pattern of a tiny molecule called a methyl group, which decorates the DNA.
“A normal cell DNA’s distinct methyl pattern is crucial to regulating its machinery and maintaining its functions. It is also responsible for turning genes on and off. Altering this pattern is one of the ways cancer cells regulate their own proliferation.
“This methyl patterning has been studied before. However, its effect in a solution (such as water) has never been explored. Using transmission electron microscopy (a high-resolution microscope), we saw that cancerous DNA fragments folded into three-dimensional structures in water. These were different to what we saw with normal tissue DNA in the water.
“In the lab, gold particles are commonly used to help detect biological molecules (such as DNA). This is because gold can affect molecular behaviour in a way that causes visible colour changes. We discovered that cancerous DNA has a strong affinity towards gold, which means it strongly binds to the gold particles.
“This finding directed us to develop a test that can detect cancerous DNA in blood and tissue. This requires a tiny amount of purified DNA to be mixed with some drops of gold particle solution. By simply observing the colour change, it is possible to identify the cancerous DNA with the naked eye within five minutes.
“The test also works for electrochemical detection – when the DNA is attached onto flat gold electrodes. Since cancer DNA has higher affinity to gold, it provides a higher relative electrochemical current signal in comparison to normal DNA. This electrochemical method is highly sensitive and could also eventually be used as a diagnostic tool.
“For this test to work properly the DNA must be pure. So far we have tested more than 200 tissue and blood samples, with 90% accuracy. Accuracy is important to ensure there are fewer false positives – wrongly detecting cancer when there is none.
“The types of cancers we tested included breast, prostate, bowel and lymphoma. We have not yet tested other cancers, but because the methylation pattern is similar across all cancers it is likely the DNA will respond in the same way.
“It is a promising start, though further analysis with more samples is needed to prove its clinical use.
“The next step is to do a large clinical study to understand how early a cancer can be detected based on this novel DNA signature. We are assessing the possibility to detect different cancer types from different body fluids from early to later stages of cancer.
“We are also considering whether the test could help monitor treatment responses based on the abundance of DNA signatures in body fluid during treatment.”
[link url="https://www.uq.edu.au/news/article/2018/12/nano-signature-discovery-could-revolutionise-cancer-diagnosis"]The University of Queensland material[/link]
[link url="https://www.nature.com/articles/s41467-018-07214-w"]Nature Communications abstract[/link]
[link url="https://theconversation.com/one-test-to-diagnose-them-all-researchers-exploit-cancers-unique-dna-signature-108078"]The Conversation report[/link]