title: Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients.
abstract: OBJECTIVE
  Single nucleotide polymorphisms (SNPs) in angiogenesis-associated genes might play an important role in activity of the tyrosine kinase inhibitor sunitinib and could affect survival of cancer patients treated with this drug. The aim of this retrospective study was to elucidate the role of 10 known SNPs in VEGFA, VEGFR1, VEGFR2 and VEGFR3 as potential prognostic and predictive markers in an independent cohort of patients with metastatic renal cell carcinoma (mRCC).
  
  
  METHODS
  DNA from 121 mRCC patients treated with sunitinib was used to analyze SNPs by TaqMan genotyping assays. Disease control rate was evaluated according to RECIST. Adverse effects of sunitinib were registered from medical records. The results of Cox and logistic regression were verified by correction for multiple testing.
  
  
  RESULTS
  Kaplan-Meier analysis revealed a reduced progression-free survival in patients with the wild-type (WT) allele of the VEGFA SNP rs699947 compared to variant alleles. Patients with the AA/AC-alleles of the VEGFR1 SNP rs9582036 had an improved median overall survival compared to those with the CC-WT allele what could be confirmed by multivariable Cox proportional hazard regression analyses. No statistically significant associations between the analyzed SNPs and higher risk for adverse effects were observed.
  
  
  CONCLUSIONS
  The results of this study suggest that most of the selected SNPs in angiogenesis-related genes are not associated with survival of mRCC patients after sunitinib therapy or with adverse effects. Only the VEGFR1 SNP rs9582036 showed a statistically significant association with overall survival. The potential of SNPs as prognostic and predictive markers for sunitinib-treated mRCC patients should be finally assessed by prospective studies.
authors.affiliation: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Juana
authors.initials: J
authors.lastname: Dornbusch
authors.affiliation: Department of Urology, University Hospital of Jena, Lessingstr. 1, 07743, Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Walter
authors.affiliation: Institute for Medical Informatics and Biometry, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gottschalk
authors.affiliation: Department of Urology, University Hospital of Jena, Lessingstr. 1, 07743, Jena, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Obaje
authors.affiliation: Department of Urology, Saarland University Medical Center, Kirrberger Str. 1, 66424, Homburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Junker
authors.affiliation: Department of Urology, Saarland University Medical Center, Kirrberger Str. 1, 66424, Homburg, Germany.
authors.forename: Carsten-Henning
authors.initials: CH
authors.lastname: Ohlmann
authors.affiliation: Institute of Pathology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Meinhardt
authors.affiliation: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Zacharis
authors.affiliation: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zastrow
authors.affiliation: Cancer Epidemiology, University Cancer Center Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Schoffer
authors.affiliation: Department of Urology, University Hospital of Jena, Lessingstr. 1, 07743, Jena, Germany.
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Grimm
authors.affiliation: Cancer Epidemiology, University Cancer Center Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Stefanie J
authors.initials: SJ
authors.lastname: Klug
authors.affiliation: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.affiliation: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. susanne.fuessel@uniklinikum-dresden.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fuessel
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib
keywords: FLT1; FLT4; KDR; SNP; Sunitinib; VEGFA; VEGFR; mRCC