RHCG and TCAF1 promoter hypermethylation predicts biochemical recurrence in prostate cancer patients treated by radical prostatectomy.

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.

Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness.

OBJECTIVES: To determine the prevalence of the HOXB13 G84E mutation (rs138213197) in Danish men with or without prostate cancer (PCa) and to investigate possible correlations between HOXB13 mutation status and clinicopathological characteristics associated with tumour aggressiveness. MATERIALS AND METHODS: We conducted a case-control study including 995 men with PCa (cases) who underwent radical prostatectomy (RP) between 1997 and 2011 at the Department of Urology, Aarhus University Hospital, Denmark. As controls, we used 1622 healthy men with a normal prostate specific antigen (PSA) level. RESULTS: The HOXB13 G84E mutation was identified in 0.49% of controls and in 2.51% of PCa cases. The mutation was associated with a 5.12-fold increased relative risk (RR) of PCa (95% confidence interval [CI] 2.26-13.38; P = 13 × 10(-6) ). Furthermore, carriers of the risk allele were significantly more likely to have a higher PSA level at diagnosis (mean PSA 19.9 vs 13.6 ng/mL; P = 0.032), a pathological Gleason score ≥7 (83.3 vs 60.9%; P = 0.032), and positive surgical margins (56.0 vs 28.5%; P = 0.006) than non-carriers. Risk allele carriers were also more likely to have aggressive disease (54.2 vs 28.6%; P = 0.011), as defined by a preoperative PSA ≥20 ng/mL, pathological Gleason score ≥ (4+3) and/or presence of regional/distant disease. At a mean follow-up of 7 months, we found no significant association between HOXB13 mutation status and biochemical recurrence in this cohort of men who underwent RP. CONCLUSIONS: This is the first study to investigate the HOXB13 G84E mutation in Danish men. The mutation was detected in 0.49% of controls and in 2.51% of cases, and was associated with 5.12-fold increased RR of being diagnosed with PCa. In our RP cohort, HOXB13 mutation carriers were more likely to develop aggressive PCa. Further studies are needed to assess the potential of HOXB13 for future targeted screening approaches.