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199 Prediction of targeted therapy response in metastatic renal cell carcinoma by DNA methylation markers
199
Prediction of targeted therapy response in metastatic renal cell carcinoma by DNA methylation markers Eur Urol Suppl 2014;13;e199
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Peters I.1 , Dubrowinskaja N.1 , Abbas M. 2 , Seidel C.3 , Kogosov M. 1 , Scherer R.4 , Gebauer K. 1 , Merseburger A.S.1 , Kuczyk M.A.1 , Gruenwald V. 5 , Serth J. 1 1 Hanover
Medical School, Dept. of Urology, Hanover, Germany, 2 Hanover Medical School, Dept. of Pathology, Hanover, Germany,
3 University 4 Hanover
Medical Center Eppendorf, Dept. of Oncology/Hematology/Bone Marrow Transplantation/Pneumology, Hamburg, Germany,
Medical School, Dept. of Biometry, Hanover, Germany, 5 Hanover Medical School, Clinic for Hematology, Hemostasis, Oncology
and Stem Cell Transplantation, Hanover, Germany INTRODUCTION & OBJECTIVES: Antiangiogenic therapy has demonstrated to increase progression-free (PFS) as well as overall survival (OS) in RCC patients, though the clinical outcome is still poor. Several clinical scoring systems help to stratify patients for optimal treatment regimes, however, identification of molecular markers would greatly improve the individualized therapy stratification. We investigated whether DNA hypermethylation based markers can predict the PFS following first-line therapy. MATERIAL & METHODS: We retrospectively examined primary tumors from formalin-fixed paraffin embedded tissue specimens obtained from 18 patients receiving anti-VEGF based targeted therapy. Quantitative methylation-specific PCRs were carried out following bisulphite conversion of DNA for CpG island methylation analysis of the five candidate genes, CST6, GATA5, LAD1, hsa-miR124-3 and hsa-miR9.1 identified in advance by others and our group as potential prognosticators for RCC. For Kaplan Meier survival analysis relative methylation values were uniformly dichotomized and log rank statistics were calculated. The analyses of sensitivity and specificity were carried out using a cut off of 6 months for PFS to categorize for therapy failure and response. RESULTS: Hypermethylation of CST6 and LAD1 shows a highly significant association with a shortened PFS following first-line therapy (p=0.009, p=0.004, log rank test). The median survival observed for the high and low methylation group was 2.0 and 11.4 months for CST6 and LAD1. LAD1 methylation showed a specificity of 1.0 (0.65-1.0, 95%CI) and a sensitivity of 0.73 (0.43-0.90, 95%CI) for the detection of therapy failure. For CST6 methylation analysis a specificity of 0.86 (0.49-0.97, 95%CI) and a sensitivity of 0.82 (0.52-0.95, 95%CI) was detected. CONCLUSIONS: CGI methylation of CST6 and LAD1 may serve as predictors for the clinical outcome of patients after anti-VEGF therapy. If these results could be confirmed in a independent evaluation group, the detection of hypermethylated loci in primary RCC would allow, to our knowledge for the first time, a molecular-based clinical management of mRCC patients.
Prediction of targeted therapy response in metastatic renal cell carcinoma by DNA methylation markers Eur Urol Suppl 2014;13;e199
Print! Print!
Peters I.1 , Dubrowinskaja N.1 , Abbas M. 2 , Seidel C.3 , Kogosov M. 1 , Scherer R.4 , Gebauer K. 1 , Merseburger A.S.1 , Kuczyk M.A.1 , Gruenwald V. 5 , Serth J. 1 1 Hanover
Medical School, Dept. of Urology, Hanover, Germany, 2 Hanover Medical School, Dept. of Pathology, Hanover, Germany,
3 University 4 Hanover
Medical Center Eppendorf, Dept. of Oncology/Hematology/Bone Marrow Transplantation/Pneumology, Hamburg, Germany,
Medical School, Dept. of Biometry, Hanover, Germany, 5 Hanover Medical School, Clinic for Hematology, Hemostasis, Oncology
and Stem Cell Transplantation, Hanover, Germany INTRODUCTION & OBJECTIVES: Antiangiogenic therapy has demonstrated to increase progression-free (PFS) as well as overall survival (OS) in RCC patients, though the clinical outcome is still poor. Several clinical scoring systems help to stratify patients for optimal treatment regimes, however, identification of molecular markers would greatly improve the individualized therapy stratification. We investigated whether DNA hypermethylation based markers can predict the PFS following first-line therapy. MATERIAL & METHODS: We retrospectively examined primary tumors from formalin-fixed paraffin embedded tissue specimens obtained from 18 patients receiving anti-VEGF based targeted therapy. Quantitative methylation-specific PCRs were carried out following bisulphite conversion of DNA for CpG island methylation analysis of the five candidate genes, CST6, GATA5, LAD1, hsa-miR124-3 and hsa-miR9.1 identified in advance by others and our group as potential prognosticators for RCC. For Kaplan Meier survival analysis relative methylation values were uniformly dichotomized and log rank statistics were calculated. The analyses of sensitivity and specificity were carried out using a cut off of 6 months for PFS to categorize for therapy failure and response. RESULTS: Hypermethylation of CST6 and LAD1 shows a highly significant association with a shortened PFS following first-line therapy (p=0.009, p=0.004, log rank test). The median survival observed for the high and low methylation group was 2.0 and 11.4 months for CST6 and LAD1. LAD1 methylation showed a specificity of 1.0 (0.65-1.0, 95%CI) and a sensitivity of 0.73 (0.43-0.90, 95%CI) for the detection of therapy failure. For CST6 methylation analysis a specificity of 0.86 (0.49-0.97, 95%CI) and a sensitivity of 0.82 (0.52-0.95, 95%CI) was detected. CONCLUSIONS: CGI methylation of CST6 and LAD1 may serve as predictors for the clinical outcome of patients after anti-VEGF therapy. If these results could be confirmed in a independent evaluation group, the detection of hypermethylated loci in primary RCC would allow, to our knowledge for the first time, a molecular-based clinical management of mRCC patients.