A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients

Iris J.H. Van Vlodrop, Sophie C. Joosten, Tim De Meyer, Kim M. Smits, Leander Van Neste, Veerle Melotte, Marcella M.L.L. Baldewijns, Leo J. Schouten, Piet A. Van Den Brandt, Jana Jeschke, Joo Mi Yi, Kornel E. Schuebel, Nita Ahuja, James G. Herman, Maureen J. Aarts, Fred T. Bosman, Wim Van Criekinge, Manon Van Engeland

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Experimental Design:Weintegrated 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 (n = 150 and n = 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, HarrellC statistic and the Akaike Information Criterion were used. Results: We identified four methylation markers, that is, GREM1, NEURL, LAD1, and NEFH, 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). Conclusions: A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts outcome of patients with ccRCC and might be used to improve current prognostic models.

LanguageEnglish (US)
Pages2006-2018
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number8
DOIs
StatePublished - Apr 15 2017

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Renal Cell Carcinoma
Methylation
Cell Survival
Genes
Confidence Intervals
decitabine
Survival
Atlases
Oligonucleotide Array Sequence Analysis
Proportional Hazards Models
Epigenomics
Research Design
Biomarkers
Genome
RNA
Cell Line
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Van Vlodrop, I. J. H., Joosten, S. C., De Meyer, T., Smits, K. M., Van Neste, L., Melotte, V., ... Van Engeland, M. (2017). A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients. Clinical Cancer Research, 23(8), 2006-2018. DOI: 10.1158/1078-0432.CCR-16-1236

A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients. / 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.

In: Clinical Cancer Research, Vol. 23, No. 8, 15.04.2017, p. 2006-2018.

Research output: Contribution to journalArticle

Van Vlodrop, IJH, Joosten, SC, De Meyer, T, Smits, KM, Van Neste, L, Melotte, V, Baldewijns, MMLL, Schouten, LJ, Van Den Brandt, PA, Jeschke, J, Yi, JM, Schuebel, KE, Ahuja, N, Herman, JG, Aarts, MJ, Bosman, FT, Van Criekinge, W & Van Engeland, M 2017, 'A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients' Clinical Cancer Research, vol 23, no. 8, pp. 2006-2018. DOI: 10.1158/1078-0432.CCR-16-1236
Van Vlodrop IJH, Joosten SC, De Meyer T, Smits KM, Van Neste L, Melotte V et al. A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients. Clinical Cancer Research. 2017 Apr 15;23(8):2006-2018. Available from, DOI: 10.1158/1078-0432.CCR-16-1236
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. / A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 8. pp. 2006-2018
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abstract = "Purpose: 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. Experimental Design:Weintegrated 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 (n = 150 and n = 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, HarrellC statistic and the Akaike Information Criterion were used. Results: We identified four methylation markers, that is, GREM1, NEURL, LAD1, and NEFH, 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). Conclusions: A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts outcome of patients with ccRCC and might be used to improve current prognostic models.",
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T1 - A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients

AU - Van Vlodrop,Iris J.H.

AU - Joosten,Sophie C.

AU - De Meyer,Tim

AU - Smits,Kim M.

AU - Van Neste,Leander

AU - Melotte,Veerle

AU - Baldewijns,Marcella M.L.L.

AU - Schouten,Leo J.

AU - Van Den Brandt,Piet A.

AU - Jeschke,Jana

AU - Yi,Joo Mi

AU - Schuebel,Kornel E.

AU - Ahuja,Nita

AU - Herman,James G.

AU - Aarts,Maureen J.

AU - Bosman,Fred T.

AU - Van Criekinge,Wim

AU - Van Engeland,Manon

PY - 2017/4/15

Y1 - 2017/4/15

N2 - Purpose: 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. Experimental Design:Weintegrated 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 (n = 150 and n = 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, HarrellC statistic and the Akaike Information Criterion were used. Results: We identified four methylation markers, that is, GREM1, NEURL, LAD1, and NEFH, 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). Conclusions: A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts outcome of patients with ccRCC and might be used to improve current prognostic models.

AB - Purpose: 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. Experimental Design:Weintegrated 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 (n = 150 and n = 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, HarrellC statistic and the Akaike Information Criterion were used. Results: We identified four methylation markers, that is, GREM1, NEURL, LAD1, and NEFH, 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). Conclusions: A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts outcome of patients with ccRCC and might be used to improve current prognostic models.

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