RHCG and TCAF1 promoter hypermethylation predicts biochemical recurrence in prostate cancer patients treated by radical prostatectomy
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Siri H. Strand1, Michal Switnicki1, Mia Moller1, Christa Haldrup1, Tine M. Storebjerg1,2,3, Jakob Hedegaard1, Iver Nordentoft1, Soren Hoyer2, Michael Borre3, Jakob S. Pedersen1, Peter J. Wild4, Jong Y. Park5, Torben F. Orntoft1 and Karina D. Sorensen1
1 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
2 Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark
3 Department of Urology, Aarhus University Hospital, Aarhus, Denmark
4 Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
5 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
Karina D. Sorensen, email:
Keywords: prostate cancer, DNA methylation, biomarker, diagnosis, prognosis
Received: December 14, 2016 Accepted: December 18, 2016 Published: December 30, 2016
Purpose: 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.
Experimental design: 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).
Results: 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).
Conclusion: 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.
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