title: RHCG and TCAF1 promoter hypermethylation predicts biochemical recurrence in prostate cancer patients treated by radical prostatectomy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Siri H
authors.initials: SH
authors.lastname: Strand
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michal
authors.initials: M
authors.lastname: Switnicki
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mia
authors.initials: M
authors.lastname: Moller
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christa
authors.initials: C
authors.lastname: Haldrup
authors.affiliation: 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.
authors.forename: Tine M
authors.initials: TM
authors.lastname: Storebjerg
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hedegaard
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Soren
authors.initials: S
authors.lastname: Hoyer
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Jong Y
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karina D
authors.initials: KD
authors.lastname: Sorensen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D019175:DNA Methylation; D003718:Denmark; D044127:Epigenesis, Genetic; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D016019:Survival Analysis; D013557:Switzerland; D014481:United States
chemical_list: D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C413213:RHCG protein, human; C000595834:TRPM8 channel-associated factor 1 protein, human
keywords: DNA methylation; biomarker; diagnosis; prognosis; prostate cancer