Abstract 1355: Clinical utility of DNA methylation markers for prostate cancer detection and prognosis: Towards less-invasive molecular diagnostic tests
Authors: Moller Mia , Haldrup Christa , Borre Michael , Hoyer Soren , Orntoft Torben , Sorensen Karina D. 
Published: May 2015

This project aims to develop new epigenetic biomarkers that can improve the accuracy of prostate cancer (PC) diagnosis and prognosis through a non/minimally-invasive molecular diagnostic test. Excessive use of prostate specific antigen (PSA) testing combined with the continued lack of accurate prognostic tools has led to overdiagnosis and overtreatment of many indolent prostate tumors. Hence, there is an urgent need for better PC biomarkers and for their translation into clinically useful tests. We have recently identified six novel genes that were hypermethylated in PC (C1orf114, HAPLN3, MOB3B, KLF8, GAS6, and AOX1) and, furthermore, developed and validated a three-gene DNA methylation signature that predicted time to PSA recurrence after radical prostatectomy (RP) in two large PC patient cohorts independently of clinicopathological parameters (Haldrup et al. 2013, J Clin Oncol). While our earlier work was based on analysis of post-operative tissue specimens, we now assess the feasibility of transferring these candidate markers to urine, plasma, or prostate needle biopsies.

Using quantitative methylation-specific PCR (qMSP), we have determined the methylation level for each of the six candidate genes in histologically malignant vs. non-malignant prostate needle biopsies from a total of 49 patients referred to biopsy due to suspicion of PC. Ten random prostate biopsies were taken from each patient: 31 of the patients had PC in at least one biopsy, 18 patients had exclusively cancer-negative biopsies. For all six genes, the DNA methylation level was significantly higher in cancer-positive compared to cancer-negative biopsies (AUC: 0.95-1.00), confirming our previous results from RP specimens. Notably, for two of the genes (HAPLN3 and GAS6), we found a significantly (p&lt;0.025) higher methylation level in histologically cancer-negative biopsies from patients with PC in at least one other biopsy compared to patients with exclusively cancer-negative biopsies, indicating the existence of a cancer field effect. A similar trend was observed for AOX1, but was not statistically significant (p=0.08) in this relatively small sample set. Detection of epigenetic field cancerization in histologically benign prostate needle biopsies may increase the sensitivity for PC detection and thereby predict the need for repeat biopsy in men with initial cancer-negative biopsies. We are currently investigating this further in a larger patient sample set. In addition, qMSP analyses of urine and plasma samples from patients with BPH, localized or advanced PC, respectively, are ongoing and the results will be presented at the conference. The development of novel and more accurate diagnostic and/or prognostic PC biomarkers, suitable for detection in non/minimally invasive samples, would be a major improvement to the clinical management of PC by allowing better and more personalized treatment strategies.

Citation Format: Mia Moller, Christa Haldrup, Michael Borre, Soren Hoyer, Torben Orntoft, Karina D. Sorensen. Clinical utility of DNA methylation markers for prostate cancer detection and prognosis: Towards less-invasive molecular diagnostic tests. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1355. doi:10.1158/1538-7445.AM2014-1355