Evaluating liquid biopsies for methylomic profiling of prostate cancer

Abstract

Background: Liquid biopsies offer significant potential for informing on cancer progression and therapeutic resistance via minimally invasive serial monitoring of genetic alterations. Although the cancer epigenome is a central driving force in most neoplasia, the accuracy of monitoring the tumor methylome using liquid biopsies remains relatively unknown. Objectives: to investigate how well two types of liquid biopsy (urine and blood) capture the prostate cancer methylome, and may thus serve as a non-invasive surrogate for studying the tumor epigenome. Methods: A cohort of four metastatic treatment naïve prostate cancer (PCa) patients was selected. Matched biopsy cores (tumor and histologically matched-normal), post-DRE, pre-biopsy urine, and peripheral blood plasma were available for each subject. DNA methylation was profiled utilizing the Infinium® MethylationEPIC BeadChip (Illumina) and analysed using the RnBeads software. Significantly (FDR adjusted P < 0.05) differentially methylated probes (DMPs) between tumor and MN were identified and examined in the liquids (done at a grouped and individual subject level). Results: DNA methylation analysis of urine and blood in men with metastatic PCa showed highly correlated patterns between the different liquid types (ρ = 0.93, P < 0.0001), with large contributions from non-tumor sources. DNA methylation profiles of liquids were more similar between subjects, than intra-individual liquid-tumor correlations. Overall, both urine and plasma are viable surrogates for tumor tissue biopsies, capturing up to 39.40% and 64.14% of tumor-specific methylation alterations, respectively. Conclusion: We conclude that both urine and blood plasma are easily accessible and sensitive biofluids for the study of PCa epigenomic alterations.

A microfluidics-assisted methodology for label-free isolation of CTCs with downstream methylation analysis of cfDNA in lung cancer

“…cfDNA is a well-known promising biomarker, under study for diagnostic and precision therapy purposes 62 . Because aberrant DNA methylation of cancer-related genes develops very early during tumorigenesis, its evaluation might be used for LC detection and subtyping 23, 63–65 . Microfluidics have been increasingly applied in liquid biopsies and may improve cancer biomarkers extraction and enrichment from biological fluids.…”

“…Because aberrant DNA methylation of cancer-related genes develops very early during tumorigenesis, its evaluation might be used for LC detection and subtyping 23,[63][64][65] . Microfluidics have been increasingly…”

Circulating tumour DNA — looking beyond the blood

“…These results might be explained by a number of patients in the control group having conditions, such as calculi or renal tract inflammation, that might have led to increased cfDNA shedding into urine, leading to false-positive results. Emerging interest exists in the analysis of epigenetic alterations, including DNA methylation, in ucfDNA obtained from men with prostate cancer 62 .…”

Detection and relevance of epigenetic markers on ctDNA: recent advances and future outlook

“…Tests based on DNA methylation markers in cfDNA are highly promising for early detection since they are minimally invasive, highly specific, and can be detected at very early stages of the disease. These epigenetic alterations can be detected in both plasma and urine of prostate cancer patients [43]. In localized and de novo metastatic prostate cancer, three genes, DOCK2, HAPLN3, and FBXO30, were found to be specifically hypermethylated in prostate cancer tissues using MS-ddPCR [44].…”