Methylation Profiling Defines an Extensive Field Defect in Histologically Normal Prostate Tissues Associated with Prostate Cancer

Abstract

Prostate cancer (PCa) is typically found as a multifocal disease suggesting the potential for molecular defects within the morphologically normal tissue. The frequency and spatial extent of DNA methylation changes encompassing a potential field defect are unknown. A comparison of non-tumor-associated (NTA) prostate to histologically indistinguishable tumor-associated (TA) prostate tissues detected a distinct profile of DNA methylation alterations (0.2%) using genome-wide DNA arrays based on the Encyclopedia of DNA Elements 18 sequence that tile both gene-rich and poor regions. Hypomethylation (87%) occurred more frequently than hypermethylation (13%). Several of the most significantly altered loci (CAV1, EVX1, MCF2L, and FGF1) were then used as probes to map the extent of these DNA methylation changes in normal tissues from prostates containing cancer. In TA tissues, the extent of methylation was similar both adjacent (2 mm) and at a distance (>1 cm) from tumor foci. These loci were also able to distinguish NTA from TA tissues in a validation set of patient samples. These mapping studies indicate that a spatially widespread epigenetic defect occurs in the peripheral prostate tissues of men who have PCa that may be useful in the detection of this disease.

Common gene pathways and families altered by DNA methylation in breast and prostate cancers

“…Methylation, 5-aza re-expression, and chromatin mapping data from LNCaP and PrEC cells, together with clinical methylation and expression data, also demonstrated that promoter methylation regulates alternative transcript expression for the known cancer-related genes RASSF1, NDRG2, and APC (Kim et al 2011a). A recent study not only identified differential DNA methylation changes between non-malignant and tumor tissue but also identified DNA methylation changes in histologically non-malignant tissue adjacent to tumor (Yang et al 2013). This highlights the critical nature of sample choice, particularly with respect to non-malignant tissue for comparison.…”

Are biomarkers evaluated in biopsy specimens predictive of prostate cancer aggressiveness?

“…The role of gene methylation in cancer progression is well documented. In particular, several epigenetic defects have been found by evaluating methylation profile of PCa tissue (Yang et al 2013) and there is evidence for increased methylation profiles in advanced PCa (Lin et al 2013). In particular, there are studies indicating an association between epigenetic downregulation of androgen receptor (Schayek et al 2010) and of SERPINB5 (Li et al 2006;Domann et al 2000;Hurtubise and Momparler 2004) expression in tumor specimens and PCa progression.…”

Global Hypomethylation (LINE-1) and Gene-Specific Hypermethylation (GSTP1) on Initial Negative Prostate Biopsy as Markers of Prostate Cancer on a Rebiopsy

“…Global DNA hypomethylation represents a genome-wide loss of DNA methylation in regions where it usually occurs and long interspersed nuclear elements-1 (LINE-1) methylation is often used as a surrogate of global DNA hypomethylation (13,14). Both GSTP1 hypermethylation and LINE-1 hypomethylation can successfully differentiate tumor from nontumor prostate tissue (12,15), and, in line with the field effect concept, they can be found in non-neoplastic tissue adjacent to tumor tissue (16)(17)(18). GSTP1 methylation alterations can also be detected in histologically negative biopsy samples and can be used to improve the sensitivity of the standard histology work-up for prostate cancer detection (19).…”