title: A germline mutation in PBRM1 predisposes to renal cell carcinoma.
abstract: BACKGROUND
  Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC.
  
  
  METHODS
  We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene.
  
  
  RESULTS
  A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours.
  
  
  CONCLUSIONS
  We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Département de Médecine Oncologique, Consultation d'Oncogénétique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Benusiglio
authors.affiliation: Ecole Pratique des Hautes Etudes, Paris, France Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Couvé
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Service de Génétique Médicale, CHU de Poitiers, Poitiers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Deveaux
authors.affiliation: Ecole Pratique des Hautes Etudes, Paris, France Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Le Jeune
authors.affiliation: Ecole Pratique des Hautes Etudes, Paris, France Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Da Costa
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, INSERM UMR1069, CHRU de Tours, Tours, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Fromont
authors.affiliation: Département d'Anatomie et de Cytologie Pathologique, Centre Hospitalier de Niort, Niort, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Memeteau
authors.affiliation: Service de Pathologie, CHU Pellegrin de Bordeaux, Bordeaux, France.
authors.forename: Mokrane
authors.initials: M
authors.lastname: Yacoub
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Unité d'oncogénétique, CRLC Val-d'Aurelle, Montpellier, France Service de Génétique Médicale, Unité d'Oncogénétique, CHU de Montpellier, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupier
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Département d'Hématologie, Oncogénétique et Immunologie, CHU de Grenoble site Nord-Institut de biologie et de pathologie, Boulevard de la Chantourne, La Tronche, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Service d'Urologie, Hôpital Européen Georges-Pompidou, AP-HP,  Paris, France Université Paris-Descartes, 12 Rue de l'École de Médecine, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Méjean
authors.affiliation: Département de Médecine Oncologique, Consultation des tumeurs rénales, et INSERM U753, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Génétique Moléculaire et Clinique, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.affiliation: Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: Département de Biopathologie, Service de Génétique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blondel
authors.affiliation: Service d'Anatomie et de Cytologie Pathologiques, CHU de Poitiers, Poitiers, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Frouin
authors.affiliation: NCCS-VARI Translational Research Laboratory, Division of Medical Sciences, National Cancer Centre, Singapore, Singapore Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, Singapore, Singapore.
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Service d'Anatomie Pathologique, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ferlicot
authors.affiliation: Département de Biopathologie, Service de Génétique, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.affiliation: Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Ecole Pratique des Hautes Etudes, Paris, France Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.affiliation: Ecole Pratique des Hautes Etudes, Paris, France Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
mesh_terms: D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors
keywords: Cancer: urological; Molecular genetics; PBRM1; predisposing genes