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Abstract
In the era of personalized medicine, there is an urgent need for non-invasive biomarkers to optimize the individual treatment of cancer patients. Epigenetic alterations, including DNA methylation and non-coding RNAs, are a hallmark of malignant tumors. The detection of many of these epigenetic conditions is feasible in bodily fluids, that is, blood plasma and serum, and may therefore be used for liquid biopsy. In this review, we summarize and discuss the current state of research on circulating epigenetic alterations (DNA methylation, miRNA and long non-coding RNA) in serum and plasma of patients with bladder cancer, prostate cancer, renal cell carcinoma and testicular germ cell cancer.
Financial & competing interests disclosure
D Dietrich has been an employee of, is a stockholder of and receives inventor’s compensation from Epigenomics AG (Berlin, Germany), a company that aims to commercialize DNA methylation biomarkers. D Dietrich is a co-inventor and owns patents on methylation biomarkers and related technologies. These patents are commercially exploited by Epigenomics AG. D Dietrich is a consultant for AJ Innuscreen GmbH (Berlin, Germany), a 100% daughter company of Analytik Jena AG (Jena, Germany) and receives royalties from the sale of innuCONVERT Bisulfite Kits. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Epigenetic alterations are common in human cancer and may be used as biomarkers; they are detectable in cancer patients’ blood, and thereby enable non-invasive quantification in terms of liquid biopsy.
The detection of cell-free DNA hypermethylation at various gene sites is specific for cancer patients, but the diagnostic accuracy is limited by a moderate sensitivity; multigene analysis may increase the sensitivity of an assay. However, in accordance with the concept of the CpG island methylator phenotype such multigene analysis might predominantly increase the sensitivity for CpG island methylator phenotype-positive tumors at the expense of a loss of overall specificity. A panel of biomarkers with different biological background (i.e., DNA methylation, somatic mutations, non-coding RNAs and autoantibodies) might be promising.
Different tumor entities have overlapping DNA hypermethylation profiles, thus the specificity of DNA methylation for a tumor entity is lower than previously expected.
The analysis of cell-free GSTP1 DNA hypermethylation has the potential to adjunct prostate-specific antigen testing. However, laboratory assays for diagnostic use are not commercially available.
The miRNA miR-141 is indicative of aggressive prostate cancer, and may be useful for identifying patients at risk for cancer progression and disease monitoring.
A miRNA panel (miR-152, miR-148b, miR-3187, miR-15b, miR-27a and miR-30a) may significantly improve diagnostics compared to conventional urine cytology in bladder cancer patients.
An increase in miR-371 in serum is highly specific for testicular germ cell cancer patients; furthermore it is detectable in most testicular cancer patients. The diagnostic accuracy seems to be considerably improved in comparison to the conventional tumor markers α-fetoprotein and human chorionic gonadotropin.
The analysis of epigenetic alterations requires standardized sample preparation and more robust and precise detection methods; the evaluation of biomarker tests in large-scale and clinically relevant cohorts is still warranted for all epigenetic biomarkers in order to establish an approvable diagnostic test for urological malignancies.
