Epigenetic markers of prostate cancer in plasma circulating DNA

Abstract

Epigenetic differences are a common feature of many diseases, including cancer, and disease-associated changes have even been detected in bodily fluids. DNA modification studies in circulating DNA (cirDNA) may lead to the development of specific non-invasive biomarkers. To test this hypothesis, we investigated cirDNA modifications in prostate cancer patients with locally confined disease (n = 19), in patients with benign prostate hyperplasias (n = 20) and in men without any known prostate disease (n = 20). This initial discovery screen identified 39 disease-associated changes in cirDNA modification, and seven of these were validated using the sodium bisulfite-based mapping of modified cytosines in both the discovery cohort and an independent 38-patient validation cohort. In particular, we showed that the DNA modification of regions adjacent to the gene encoding ring finger protein 219 distinguished prostate cancer from benign hyperplasias with good sensitivity (61%) and specificity (71%). We also showed that repetitive sequences detected in this study were meaningful, as they indicated a highly statistically significant loss of DNA at the pericentromeric region of chromosome 10 in prostate cancer patients (p = 1.8 × 10(-6)). Based on these strong univariate results, we applied machine-learning techniques to develop a multi-locus biomarker that correctly distinguished prostate cancer samples from unaffected controls with 72% accuracy. Lastly, we used systems biology techniques to integrate our data with publicly available DNA modification and transcriptomic data from primary prostate tumors, thereby prioritizing genes for further studies. These data suggest that cirDNA epigenomics are promising source for non-invasive biomarkers.

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease

“…The ability to detect cancer or estimate cancer risk from normal tissue, stool, peripheral blood, or other body fluids (such as sputum and urine) has become the holy grail of biomarker discovery. 342 Biomarkers in normal tissue, stool, or body fluids can represent: 1) a pathological outcome, analogous to established serum tumor markers; 2) a surrogate or shared indicator of etiologic exposure and disease predisposition; or 3) an intermediary in a causal pathway from etiology to downstream outcome (cancer incidence or behavior). Analysis of normal tissue, stool, and body fluids can expand the scope of, and add a novel dimension to MPE research (Figure 3).…”

The Clinical Utilization of Circulating Cell Free DNA (CCFDNA) in Blood of Cancer Patients

“…This feature could correspond well with tumor activity. Thus, CCFDNA can be an important noninvasive and useful biomarker especially for follow up in patients with prostate cancer [215–218]. …”

Epigenetic and Circulating Biomarkers: Future Analytes for Liquid Biopsies

“…Cortese et al studied circulating free DNA in prostate cancer patients [3]. In this study, circulating DNA (ctDNA) modifications collected from prostate cancer patients with locally confined disease (19 patients), in patients with benign prostate hyperplasias (20 patients), and in men without any known prostate disease (20 patients) were studied after isolation of ctDNA from plasma.…”

“…In this study, circulating DNA (ctDNA) modifications collected from prostate cancer patients with locally confined disease (19 patients), in patients with benign prostate hyperplasias (20 patients), and in men without any known prostate disease (20 patients) were studied after isolation of ctDNA from plasma. DNA methylation in these ctDNA samples were studied via the bisulfite method [3]. The data showed that, when assayed via the analysis of ctDNA, the greatest difference between prostate cancer patients and controls was located at RNF219 (gene encoding ring-finger protein 219) on chromosome 13q31.1.…”