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, Leander Van Neste, Wim Van Criekinge, Hein Van Poppel, Evelyne Lerut, Kornel Schuebel, Nita Ahuja, James G. Herman, Adriaan P. De Bruïne, Manon Van Engeland

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)575-584
Number of pages10
JournalAmerican Journal of Pathology
Volume176
Issue number2
DOIs
StatePublished - Feb 2010

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CpG Islands
Renal Cell Carcinoma
Methylation
Confidence Intervals
Neoplasms
Multivariate Analysis
Cell Line
Bone Morphogenetic Proteins
Survival
Carcinogenesis
Endothelial Cells
Polymerase Chain Reaction
Messenger RNA
Population
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Van Vlodrop, I. J. H., Baldewijns, M. M. L., Smits, K. M., Schouten, L. J., Van Neste, L., Van Criekinge, W., ... Van Engeland, M. (2010). Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma. American Journal of Pathology, 176(2), 575-584. https://doi.org/10.2353/ajpath.2010.090442

Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma. / Van Vlodrop, Iris J H; Baldewijns, Marcella M L; Smits, Kim M.; Schouten, Leo J.; Van Neste, Leander; Van Criekinge, Wim; Van Poppel, Hein; Lerut, Evelyne; Schuebel, Kornel; Ahuja, Nita; Herman, James G.; De Bruïne, Adriaan P.; Van Engeland, Manon.

In: American Journal of Pathology, Vol. 176, No. 2, 02.2010, p. 575-584.

Research output: Contribution to journalArticle

Van Vlodrop, IJH, Baldewijns, MML, Smits, KM, Schouten, LJ, Van Neste, L, Van Criekinge, W, Van Poppel, H, Lerut, E, Schuebel, K, Ahuja, N, Herman, JG, De Bruïne, AP & Van Engeland, M 2010, 'Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma', American Journal of Pathology, vol. 176, no. 2, pp. 575-584. https://doi.org/10.2353/ajpath.2010.090442
Van Vlodrop, Iris J H ; Baldewijns, Marcella M L ; Smits, Kim M. ; Schouten, Leo J. ; Van Neste, Leander ; Van Criekinge, Wim ; Van Poppel, Hein ; Lerut, Evelyne ; Schuebel, Kornel ; Ahuja, Nita ; Herman, James G. ; De Bruïne, Adriaan P. ; Van Engeland, Manon. / Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma. In: American Journal of Pathology. 2010 ; Vol. 176, No. 2. pp. 575-584.
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abstract = "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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AU - Schouten, Leo J.

AU - Van Neste, Leander

AU - Van Criekinge, Wim

AU - Van Poppel, Hein

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AU - Schuebel, Kornel

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N2 - 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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