title: Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting.
abstract: OBJECTIVE
  Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib.
  
  
  METHODS
  We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel-Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib.
  
  
  RESULTS
  Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands.
  
  
  CONCLUSIONS
  ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs.
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Beuselinck
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Job
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France. UMR_S1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Becht
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Karadimou
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants malades, Department of Pathology, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. UMR_S1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Giraldo
authors.affiliation: Department of Pathology, CHU Rennes, Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.affiliation: Department of Pathology, Clinique St-Joseph, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Molinié
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Department of Pathology, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France.
authors.forename: Reza
authors.initials: R
authors.lastname: Elaidi
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Teghom
authors.affiliation: Department of Urology, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Patard
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Méjean
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France. UMR_S1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Wolf Herman
authors.initials: WH
authors.lastname: Fridman
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France. UMR_S1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France. jessica.zucman-rossi@inserm.fr.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000145:classification* / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib