In the past couple of years, our group has been investigating circulating miRNAs as potential liquid biopsy (LB) biomarkers of cancer. We showed that total levels of cf-miRNA were a powerful diagnostic and prognostic tool in breast cancer (1) and we could also show the diagnostic ability of a panel of miRNAs in ovarian cancer (OC) (2).
In our most recent study, we wanted to expand our LB studies to cell-free circulating DNA (cfDNA) which is gaining increasing clinical utility in oncology. In addition we have been able to confirm our LB findings with matched tumor tissues from a subset of patients. This finding is particularly interesting, since the fraction of tumor derived material in the circulation is thought to be quite low.
What did we do in this study?
Similarly to our previous work, we first looked at the total levels of cf-miRNA and cfDNA in patient plasma. Compared to healthy controls, there was a significant and similar increase of both analytes. While both cf-miRNA and cfDNA levels correlated with patient survival, only cf-miRNA was an independent prognosticator. We could show that levels of the miR-200 family were increased in both circulation and tissues of OC. Next, we found that the promoter of miR-200 was hypomethylated in cancer tissues, but not in cfDNA. This means that the miR-200 family is likely epigenetically regulated in OC tissues, which we could not confirm in the circulation.
In summary, we believe that cf-miRNAs are a more appropriate surrogate marker for OC than cfDNA. Not only is their expression reflected in the original tumor tissues, they are easily and quickly obtained from less than 1ml of patient blood and they are remarkably stable in circulation.
What is the clinical significance?
This is one of the only studies to systematically analyze cfDNA, cf-miRNA and matched tissues from the same patient cohort. The fact that the upregulation of specific miRNAs could be simultaneously shown, gives miRNA more strength as a LB marker, since specificity is a major challenge in the field. We believe that these markers might have even more prognostic impact when used for disease monitoring. Additionally, we verified that these miRNAs are epigenetically regulated in OC, which opens a discussion on the potential introduction of epigenetic therapies.
In conclusion, our data support the practicability and clinical relevance of circulating miRNAs as liquid biopsy markers and propose prognostic potential of circulating miR-200c and miR-141 for OC. Ultimately, we describe a link between miR-200c overexpression and miR-200c promoter hypomethylation in OC tissue, which warrants further investigation.