Tracking cancer epigenetics
While early liquid biopsy research efforts focused on detecting DNA sequence changes, the importance of epigenetics has recently come to the fore, says Sarah-Jane Dawson, a medical oncologist at the Peter MacCallum Cancer Centre and the University of Melbourne, who is using biomodal’s approach in her research into liquid biopsies.
As well as helping researchers identify tumour DNA amid the soup of regular cell-free DNA, the fact that different tissues have distinct methylation patterns can help explain where the cell-free DNA might be coming from. “There are many advantages to being able to study epigenomics in concert with genomic features,” says Dawson.
Until now, realizing these advantages has been difficult. Researchers wanting to analyse the epigenome had two main options. The first, long-read sequencing, doesn’t work well when only tiny amounts of DNA sample are available, as is the case with cell-free DNA from blood. The other option is bisulfite sequencing, which alters the DNA sequence of the sample, meaning it can’t be simultaneously used to detect DNA mutations. Researchers therefore have to split their sample in two and perform DNA sequencing in a separate experiment. Again, this is a problem when samples are limited.
What’s more, bisulfite sequencing cannot distinguish between different epigenetic modifications of cytosine. Methylation of cytosines in genomic regions that control gene activity result in those genes being silenced. When cells are in the process of lifting this silencing, one type of epigenetic mark called 5-methylcytosine (5mC) gets converted to another, 5-hydroxymethylcytosine (5hmC). Detecting this intermediate state would allow researchers to see which genomic regions the cell is starting to boot up. “5hmC is telling you not just that this region is open, but actually this region is opening,” says Charlesworth. “It’s giving you dynamic information.”
