title: MET is a potential target across all papillary renal cell carcinomas: result from a large molecular study of pRCC with CGH array and matching gene expression array.
abstract: OBJECTIVE
  Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in 13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC.
  
  
  METHODS
  We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC.
  
  
  RESULTS
  MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression.
  
  
  CONCLUSIONS
  The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status.
authors.affiliation: Authors' Affiliations: Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France; INSERM U753, IGR, Villejuif, France; Laurence.albiges@gustaveroussy.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Bioinformatics Unit; Functional Genomics Unit;
authors.forename: Justine
authors.initials: J
authors.lastname: Guegan
authors.affiliation: INSERM U753, IGR, Villejuif, France;
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Formal
authors.affiliation: Department of Pathology, Necker-Enfants Malades Hospital, AP-HP, Université Paris Descartes;
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.affiliation: Department of Pathology, CHU Rennes, Faculté de Médecine, Université de Rennes1, Rennes; and.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.affiliation: Department of Pathology, Tenon Hospital, AP-HP, Université Paris Pierre et Marie Curie;
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.affiliation: Department of Urology, Hopital Saint André, Bordeaux, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bernhard
authors.affiliation: Department of Pathology, Foch Hospital, Suresnes;
authors.forename: Philippe
authors.initials: P
authors.lastname: Camparo
authors.affiliation: Department of Pathology, Institut Gustave Roussy, Villejuif, France;
authors.forename: Zahira
authors.initials: Z
authors.lastname: Merabet
authors.affiliation: Department of Pathology, Hopital Saint Joseph;
authors.forename: Vincent
authors.initials: V
authors.lastname: Molinie
authors.affiliation: Department of Pathology, Hopital Mondor, Faculté Paris Sud, Creteil;
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.affiliation: Functional Genomics Unit;
authors.forename: Cedric
authors.initials: C
authors.lastname: Orear
authors.affiliation: INSERM U753, IGR, Villejuif, France; Laboratoire de Génétique Oncologique EPHE, Institut Gustave Roussy;
authors.forename: Sophie
authors.initials: S
authors.lastname: Couvé
authors.affiliation: INSERM U753, IGR, Villejuif, France; Laboratoire de Génétique Oncologique EPHE, Institut Gustave Roussy;
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
authors.affiliation: INSERM U753, IGR, Villejuif, France; Department of Urology, Kremlin Bicetre Hospital, Université Paris Sud, Kremlin Bicêtre, Paris;
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Patard
authors.affiliation: Authors' Affiliations: Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France; INSERM U753, IGR, Villejuif, France;
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D056915:DNA Copy Number Variations; D005091:Exons; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D019859:Proto-Oncogene Proteins c-met