Abstract 4341: Employing the epigenetic field effect to detect prostate cancer in biopsy-negative patients

Abstract

Abstract Purpose: Prostate cancer (PCa) is typically multifocal supporting the principle that molecular alterations can occur in histologically normal tissues in patients that have cancer. We have recently demonstrated using DNA methylation microarrays that epigenetic differences define a widespread field defect in the normal prostate tissue from men with cancer. The purpose of this study is to determine whether a novel panel of DNA methylation markers can predict the presence of PCa using fresh and paraffin-embedded histologically normal biopsy cores from multiple medical sites. Materials and Methods: Encode HG18 DNA methylation arrays, containing 385,000 probes tiling the biologically significant pilot regions of the human genome, were used to identify methylation alterations between NTA and TA tissues. Bisulfite Pyrosequencing confirmed alterations at numerous loci. Methylation was assessed using quantitative pyrosequencing in a training set consisting of 65 non-tumor associated (NTA) and tumor associated (TA) prostate tissues. A multiplex model was generated using multivariate logistic regression and externally validated in a blinded fashion using a set of 47 NTA and TA biopsy specimens from an external institution. Results: The methylation field defect was not significantly different between adjacent and distant tissues from tumor foci indicating this was not a peritumor effect. DNA methylation was analyzed in a subset of significant loci in NTA and TA tissues. Robust methylation differences were observed for all genes at all CpGs assayed (p<0.0001) in the 47 fresh-frozen specimens. Regression models incorporating individual genes (EVX1, CAV1, and FGF1) and a gene panel (EVX1 and FGF1) discriminated between NTA and TA tissues in the original training set (AUC 0.796-0.898, p<0.001). Upon external validation, uniplex models incorporating EVX1, CAV1, or FGF1 discriminated between TA and NTA biopsy-negative specimens with an AUC of 0.702, 0.696, and 0.658, respectively (p<0.05). Furthermore, a multiplex panel (EVX1 and FGF1) identified PCa patients with an AUC of 0.774 (p = 0.001) and had a negative predictive value of 0.909. Further results will be reported from an ongoing multicenter trial involving 160 FFPE specimens. Conclusions: A widespread epigenetic field defect can be utilized to detect the existence of PCa in patients with histologically negative biopsies. This assay is unique in that it detects alterations in non-tumor cells at distance from tumor foci. With further validation, this marker panel (EVX1 and FGF1) has the potential to decrease the need for repeated prostate biopsies, a costly procedure associated with pain and complications. Citation Format: Bing Yang, Johnathon McCormick, Nathan Damaschke, Anastasia Montgomery, Glen Leverson, Wei Huang, Daniel W. Lin, David F. Jarrard. Employing the epigenetic field effect to detect prostate cancer in biopsy-negative patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4341.