Germline BAP1 mutations predispose to renal cell carcinomas.
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Popova Tatiana, Hebert Lucie, Jacquemin Virginie, Gad Sophie, Caux-Moncoutier Virginie, Dubois-d'Enghien Catherine, Richaudeau Bénédicte, Renaudin Xavier, Sellers Jason, Nicolas André, Sastre-Garau Xavier, Desjardins Laurence, Gyapay Gabor, Raynal Virginie, Sinilnikova Olga M, Andrieu Nadine, Manié Elodie, de Pauw Antoine, Gesta Paul, Bonadona Valérie, Maugard Christine M, Penet Clotilde, Avril Marie-Françoise, Barillot Emmanuel, Cabaret Odile, Delattre Olivier, Richard Stéphane, Caron Olivier, Benfodda Meriem, Hu Hui-Han, Soufir Nadem, Bressac-de Paillerets Brigitte, Stoppa-Lyonnet Dominique, Stern Marc-Henri
Аннотация
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.