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Originally published online as doi:10.2353/ajpath.2010.090442 on December 30, 2009

Published online before print December 30, 2009
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(American Journal of Pathology. 2010;176:575-584.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.090442

Prognostic Significance of Gremlin1 (GREM1) Promoter CpG Island Hypermethylation in Clear Cell Renal Cell Carcinoma

Iris J.H. van Vlodrop*, Marcella M.L. Baldewijns*, Kim M. Smits*, Leo J. Schouten{dagger}, Leander van Neste{ddagger}, Wim van Criekinge{ddagger}, Hein van Poppel§, Evelyne Lerut, Kornel E. Schuebel||, Nita Ahuja||**, James G. Herman||, Adriaan P. de Bruïne* and Manon van Engeland*

From the Departments of Pathology* and Epidemiology,{dagger} GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; the Department of Molecular Biotechnology,{ddagger} Ghent University, Ghent, Belgium; the Departments of Urology§ and Pathology, University Hospital of Leuven, Leuven, Belgium; and the Division of Cancer Biology|| and Department of Surgery,** The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland

Gremlin1 (GREM1), a bone morphogenetic protein antagonist and putative angiogenesis-modulating gene, is silenced by promoter hypermethylation in human malignancies. Here we study GREM1 methylation in clear cell renal cell carcinoma (ccRCC) and its impact on tumor characteristics and clinical outcome. Three GREM1 promoter CpG island regions (i, ii, iii) were analyzed by methylation-specific PCR and/or bisulfite sequencing in ccRCC cell lines and ccRCCs from two independent patient series. Results were correlated with clinicopathological and angiogenic parameters. Bisulfite sequencing of ccRCC cell lines showed GREM1 methylation, associated with absence of GREM1 mRNA. GREM1 methylation prevalence in ccRCCs varied between regions: 55%, 24%, and 20% for regions i, ii, and iii, respectively. GREM1 region iii methylation was associated with increased tumor size (P = 0.02), stage (P = 0.013), grade (P = 0.04), tumor (P = 0.001), and endothelial cell (P = 0.0001) proliferation and decreased mean vessel density (P = 0.001) in a hospital-based ccRCC series (n = 150). In univariate analysis, GREM1 region iii methylated ccRCCs had a significant worse survival when compared with unmethylated ccRCCs (hazard ratio [HR] = 2.35, 95% confidence interval [CI]:1.29 to 4.28), but not in multivariate analysis (HR = 0.88, 95% CI: 0.45 to 1.74). In a population-based validation series (n = 185), GREM1 region iii methylation was associated with increased Fuhrman grade (P = 0.03) and decreased overall survival (P = 0.001) in univariate and multivariate analysis (HR = 2.32, 95% CI: 1.52 to 3.53 and HR = 2.27, 95% CI: 1.44 to 3.59, respectively). The strong correlation between GREM1 region iii promoter methylation and increased malignancy and its correlation with active angiogenesis indicates a role for GREM1 in ccRCC carcinogenesis and tumor angiogenesis.






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