Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome

Abstract

Purpose In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival. Experimental Design We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests. Results Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12–2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25–2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P< 0.001). Conclusions CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis.

Epigenetic biomarkers of promoter DNA methylation in the new era of cancer treatment

“…Interestingly, in primary breast cancer, CDO1 hypermethylation did not correlate significantly with markers of tumor progression such as TNM factors, while CDO1 hypermethylation was the strongest independent prognostic factor . Importantly, the prognostic relevance of CDO1 methylation was confirmed even in a prospective nationwide cohort study in the Netherlands of patients with renal cell carcinoma . These findings suggest that the methylation status of the CDO1 gene could be used as a prognostic marker in various human cancers.…”

“…Since 2010, the frequent hypermethylation of the CDO1 gene has been reported in primary breast, 33,34 lung, 19 biliary tract, 35 esophageal squamous cell carcinoma (SCC) 36 and adenocarcinoma, 37 gastric, 19 colorectal, 19,38 bladder, 19 penile (SCC), 39 kidney, 40 prostate, 41 endometrial, 42 pancreatic 43 and gallbladder cancer. 44 The frequencies of the aberrations in CDO1 methylation in these cancers are high ( Figure 3A).…”

Details matter: the role of genomic location and assay standardization in DNA methylation analyses

“…Indeed, the variation among studies using different methods was not larger than among studies using the same method [14]. In addition, we have also shown that, if carefully aligned and optimized regarding genomic location and sensitivity, multiple DNA methylation assays can yield comparable results [16] and that DNA methylation markers can be validated in independent patient series using independent technologies [17,18].…”

The epigenetic landscape of renal cancer

“…118) and SLC16A3 (also known as MCT4) 119 . SLC16A3 encodes solute carrier family 16 member 3, a monocarboxylate transporter that is essential for transport of lactate across the plasma membrane, thus maintaining cellular pH and the appropriate progression of glycolysis 119 .…”