A Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients

• Published in: Clinical cancer research Vol. 23; no. 8; pp. 2006 - 2018
• Main Authors: van Vlodrop, Iris J H, Joosten, Sophie C, De Meyer, Tim, Smits, Kim M, Van Neste, Leander, Melotte, Veerle, Baldewijns, Marcella M L L, Schouten, Leo J, van den Brandt, Piet A, Jeschke, Jana, Yi, Joo Mi, Schuebel, Kornel E, Ahuja, Nita, Herman, James G, Aarts, Maureen J, Bosman, Fred T, Van Criekinge, Wim, van Engeland, Manon
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.04.2017
• Subjects: Adult; Aged; Autoantigens - genetics; Biomarkers; Biomarkers, Tumor - genetics; Cancer; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - mortality; Cell survival; Clear cell-type renal cell carcinoma; Collagen Type XVII; Confidence intervals; Deoxyribonucleic acid; Disease-Free Survival; DNA; DNA methylation; DNA Methylation - genetics; DNA microarrays; DNA sequencing; Experimental design; Female; Gene expression; Genomes; High-Throughput Nucleotide Sequencing; Humans; Intercellular Signaling Peptides and Proteins - genetics; Kaplan-Meier Estimate; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Male; Mathematical models; Medical prognosis; Middle Aged; Neurofilament Proteins - genetics; Non-Fibrillar Collagens - genetics; Oligonucleotide Array Sequence Analysis; Patients; Prognosis; Promoter Regions, Genetic - genetics; Proportional Hazards Models; Rank tests; Ribonucleic acid; RNA; Statistical analysis; Survival; Ubiquitin-Protein Ligases - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1236

The currently used prognostic models for patients with nonmetastatic clear cell renal cell carcinoma (ccRCC) are based on clinicopathologic features and might be improved by adding molecular markers. Epigenetic alterations occur frequently in ccRCC and are promising biomarkers. The aim of this study is to identify prognostic promoter methylation markers for ccRCC. We integrated data generated by massive parallel sequencing of methyl-binding domain enriched DNA and microarray-based RNA expression profiling of 5-aza-2'-deoxycytidine-treated ccRCC cell lines to comprehensively characterize the ccRCC methylome. A selection of the identified methylation markers was evaluated in two independent series of primary ccRCC ( = 150 and = 185) by methylation-specific PCR. Kaplan-Meier curves and log-rank tests were used to estimate cause-specific survival. HRs and corresponding 95% confidence intervals (CI) were assessed using Cox proportional hazard models. To assess the predictive capacity and fit of models combining several methylation markers, Harrell statistic and the Akaike Information Criterion were used. We identified four methylation markers, that is, and , that individually predicted prognosis of patients with ccRCC. The four markers combined were associated with poorer survival in two independent patient series (HR, 3.64; 95% CI, 1.02-13.00 and HR, 7.54; 95% CI, 2.68-21.19). These findings were confirmed in a third series of ccRCC cases from The Cancer Genome Atlas (HR, 3.60; 95% CI, 2.02-6.40). A four-gene promoter methylation marker panel consisting of and predicts outcome of patients with ccRCC and might be used to improve current prognostic models. .