title: RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.
abstract: BACKGROUND
  Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs.
  
  
  METHODS
  Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression.
  
  
  RESULTS
  We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001).
  
  
  CONCLUSIONS
  RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.
authors.affiliation: Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, IUH, rue Juliette Dodu 27, F-75010 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, rue de l'Ecole de Médecine 15, F-75006 Paris, France.|Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Beuselinck
authors.affiliation: Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, IUH, rue Juliette Dodu 27, F-75010 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, rue de l'Ecole de Médecine 15, F-75006 Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Jean-Baptiste
authors.affiliation: Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, IUH, rue Juliette Dodu 27, F-75010 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, rue de l'Ecole de Médecine 15, F-75006 Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, rue Corvisart 14, F-75013 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Job
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, rue Corvisart 14, F-75013 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: De Reynies
authors.affiliation: Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Wolter
authors.affiliation: Department of Medical Oncology, Hôpital Foch, rue Worth 40, F-92150 Suresnes, France.
authors.forename: C
authors.initials: C
authors.lastname: Théodore
authors.affiliation: Department of Medical Oncology, Institut Paoli-Calmettes, 232 Boulevard de Sainte-Marguerite, F-13273 Marseille, France.
authors.forename: G
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Avenue du Maréchal de Lattre de Tassigny 51, F-94000 Créteil, France.
authors.forename: B
authors.initials: B
authors.lastname: Rousseau
authors.affiliation: Department of Medical Oncology, Institut Gustave Roussy, rue Edouard Vaillant 114, F-94800 Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Department of Urology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Joniau
authors.affiliation: Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, rue de Sèvres 149, F-75015 Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Verkarre
authors.affiliation: Department of Pathology, University Hospitals Leuven, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Lerut
authors.affiliation: Department of Urology, Hôpital Bicêtre, rue du Général Leclerc 78, F-94270 Le Kremlin-Bicêtre, France.
authors.forename: J J
authors.initials: JJ
authors.lastname: Patard
authors.affiliation: Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Department of Urology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Rue Leblanc 20, F-75015 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Méjean
authors.affiliation: Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Rue Leblanc 20, F-75015 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Elaidi
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, rue de l'Ecole de Médecine 15, F-75006 Paris, France.|Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Rue Leblanc 20, F-75015 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Oudard
authors.affiliation: Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, IUH, rue Juliette Dodu 27, F-75010 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, rue de l'Ecole de Médecine 15, F-75006 Paris, France.|Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Rue Leblanc 20, F-75015 Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D016391:Genes, src / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D053245:RANK Ligand / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D053244:Osteoprotegerin; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor