Abstract
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.
Highlights
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in men in the Western world [1]
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 Prostatespecific antigen (PSA) (HR (95% confidence interval (CI)): 2.09 (1.26 - 3.46); P = 0.004), and this was successfully validated in cohort 2 (HR: 1.81 (1.05 - 3.12); P = 0.032)
To identify novel candidate markers for prostate cancer, global DNA methylation analysis was performed in 21 T, 12 adjacent normal (AN), and 9 true normal (N) prostate tissue samples (Table S1), in addition to 3 malignant (PC3, LNCaP, 22rv1) and 2 NM (PrEC, BPH1) prostate cell lines using the Illumina Illumina Infinium HumanMethylation450 BeadChip (450K) array
Summary
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in men in the Western world [1]. The diagnosis is based on elevated serum PSA (prostate-specific antigen), suspicious digital rectal examination and histopathologic evaluation of the sampled biopsies. The currently available routine prognostic tools (mainly Gleason score (GS), serum PSA, and tumor stage) are unable to clearly distinguish aggressive from indolent disease at the time of diagnosis. Methylation of CpG dinucleotides in promoter regions is an essential mechanism of long-term gene silencing. Aberrant hypermethylation of promoter-associated CpG islands (CGIs) is a well-established mechanism for tumor suppressor gene (TSG) silencing [2]. While recurrent somatic mutations are rare in prostate cancer, aberrant promoter hypermethylation occurs early and more consistently in tumor development and progression, and constitutes a promising source for discovery of novel biomarkers. DNA methylation alterations have shown significant potential as diagnostic as well as prognostic biomarkers for prostate cancer [3]
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