title: DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies.
abstract: VEGF-targeted therapy increases both the progression-free (PFS) and overall survival (OS) of patients with metastasized renal cell cancer (mRCC). Identification of molecular phenotypes of RCC could improve risk-stratification and the prediction of the clinical disease course. We investigated whether gene-specific DNA hypermethylation can predict PFS and OS among patients undergoing anti-VEGF-based therapy. Primary tumor tissues from 18 patients receiving targeted therapy were examined retrospectively using quantitative methylation-specific PCR analysis of CST6, LAD1, hsa-miR-124-3, and hsa-miR-9-1 CpG islands. PFS and OS were analyzed for first-line and sequential antiangiogenic therapies using the log rank statistics. Sensitivity and specificity were determined for predicting first-line therapy failure. Hypermethylation of CST6 and LAD1 was associated with both a shortened PFS (log rank p = 0.009 and p = 0.004) and OS (p = 0.011 and p = 0.043). The median PFS observed for the high and low methylation groups of CST6 and LAD1 was 2.0 vs.11.4 months. LAD1 methylation had a specificity of 1.0 (95% CI 0.65-1.0) and a sensitivity of 0.73 (95% CI 0.43-0.90) for the prediction of first-line therapy. CST6 and LAD1 methylation are candidate epigenetic biomarkers showing unprecedented association with PFS and OS as well as specificity for the prediction of the response to therapy. DNA methylation markers should be considered for the prospective evaluation of larger patient cohorts in future studies.
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Peters
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Dubrowinskaja
authors.affiliation: Department of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abbas
authors.affiliation: Department of Oncology/Hematology/Bone MarrowTransplantation/Pneumology, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Seidel
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kogosov
authors.affiliation: Department of Biometry, Hannover Medical School, Hannover, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Scherer
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Gebauer
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Axel S
authors.initials: AS
authors.lastname: Merseburger
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Kuczyk
authors.affiliation: Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Grünwald
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Serth
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D016000:Cluster Analysis; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D012372:ROC Curve; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents