The lack of biomarkers that can distinguish aggressive from indolent prostate cancer has caused substantial overtreatment of clinically insignificant disease. Here, by genome-wide DNA methylome profiling, we sought to identify new biomarkers to improve the accuracy of prostate cancer diagnosis and prognosis.
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Eight novel candidate markers, COL4A6, CYBA, TCAF1 (FAM115A), HLF, LINC01341 (LOC149134), LRRC4, PROM1, and RHCG, were selected from Illumina Infinium HumanMethylation450 BeadChip analysis of 21 tumor (T) and 21 non-malignant (NM) prostate specimens. Diagnostic potential was further investigated by methylation-specific qPCR analysis of 80 NM vs. 228 T tissue samples. Prognostic potential was assessed by Kaplan-Meier, uni- and multivariate Cox regression analysis in 203 Danish radical prostatectomy (RP) patients (cohort 1), and validated in an independent cohort of 286 RP patients from Switzerland and the U.S. (cohort 2).
Hypermethylation of the 8 candidates was highly cancer-specific (area under the curves: 0.79-1.00). Furthermore, high methylation of the 2-gene panel RHCG-TCAF1 was predictive of biochemical recurrence (BCR) in cohort 1, independent of the established clinicopathological parameters Gleason score, pathological tumor stage, and pre-operative PSA (HR (95% confidence interval (CI)): 2.09 (1.26 - 3.46); P = 0.004), and this was successfully validated in cohort 2 (HR (95% CI): 1.81 (1.05 - 3.12); P = 0.032).
Methylation of the RHCG-TCAF1 panel adds significant independent prognostic value to established prognostic parameters for prostate cancer and thus may help to guide treatment decisions in the future. Further investigation in large independent cohorts is necessary before translation into clinical utility.
Oncotarget. 2016 Dec 30 [Epub ahead of print]
Siri H Strand, Michal Switnicki, Mia Moller, Christa Haldrup, Tine M Storebjerg, Jakob Hedegaard, Iver Nordentoft, Soren Hoyer, Michael Borre, Jakob S Pedersen, Peter J Wild, Jong Y Park, Torben F Orntoft, Karina D Sorensen
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark., Department of Urology, Aarhus University Hospital, Aarhus, Denmark., Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland., Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.