title: Germline BAP1 mutations predispose to renal cell carcinomas.
abstract: The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.
authors.affiliation: Institut Curie, Inserm U830, Paris 75248, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Popova
authors.forename: Lucie
authors.initials: L
authors.lastname: Hebert
authors.forename: Virginie
authors.initials: V
authors.lastname: Jacquemin
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
authors.forename: Virginie
authors.initials: V
authors.lastname: Caux-Moncoutier
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubois-d'Enghien
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Richaudeau
authors.forename: Xavier
authors.initials: X
authors.lastname: Renaudin
authors.forename: Jason
authors.initials: J
authors.lastname: Sellers
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.forename: Laurence
authors.initials: L
authors.lastname: Desjardins
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyapay
authors.forename: Virginie
authors.initials: V
authors.lastname: Raynal
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
authors.forename: Nadine
authors.initials: N
authors.lastname: Andrieu
authors.forename: Elodie
authors.initials: E
authors.lastname: Manié
authors.forename: Antoine
authors.initials: A
authors.lastname: de Pauw
authors.forename: Paul
authors.initials: P
authors.lastname: Gesta
authors.forename: Valérie
authors.initials: V
authors.lastname: Bonadona
authors.forename: Christine M
authors.initials: CM
authors.lastname: Maugard
authors.forename: Clotilde
authors.initials: C
authors.lastname: Penet
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.forename: Odile
authors.initials: O
authors.lastname: Cabaret
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.forename: Meriem
authors.initials: M
authors.lastname: Benfodda
authors.forename: Hui-Han
authors.initials: HH
authors.lastname: Hu
authors.forename: Nadem
authors.initials: N
authors.lastname: Soufir
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
mesh_terms: D000328:Adult; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase