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A germline mutation in PBRM1 predisposes to renal cell carcinoma
  1. Patrick R Benusiglio1,2,
  2. Sophie Couvé3,4,5,
  3. Brigitte Gilbert-Dussardier1,6,
  4. Sophie Deveaux1,
  5. Hélène Le Jeune3,4,5,
  6. Mélanie Da Costa3,4,5,
  7. Gaëlle Fromont7,
  8. Françoise Memeteau8,
  9. Mokrane Yacoub9,
  10. Isabelle Coupier1,10,11,
  11. Dominique Leroux1,12,
  12. Arnaud Méjean1,13,14,
  13. Bernard Escudier15,
  14. Sophie Giraud1,16,
  15. Anne-Paule Gimenez-Roqueplo17,
  16. Christophe Blondel18,
  17. Eric Frouin19,
  18. Bin T Teh20,21,22,
  19. Sophie Ferlicot1,23,
  20. Brigitte Bressac-de Paillerets18,
  21. Stéphane Richard1,3,4,5,
  22. Sophie Gad3,4,5
  1. 1Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France
  2. 2Département de Médecine Oncologique, Consultation d'Oncogénétique, Gustave Roussy Cancer Campus, Villejuif, France
  3. 3Ecole Pratique des Hautes Etudes, Paris, France
  4. 4Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France
  5. 5Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France
  6. 6Service de Génétique Médicale, CHU de Poitiers, Poitiers, France
  7. 7Service d'Anatomie et Cytologie Pathologiques, INSERM UMR1069, CHRU de Tours, Tours, France
  8. 8Département d'Anatomie et de Cytologie Pathologique, Centre Hospitalier de Niort, Niort, France
  9. 9Service de Pathologie, CHU Pellegrin de Bordeaux, Bordeaux, France
  10. 10Unité d'oncogénétique, CRLC Val-d'Aurelle, Montpellier, France
  11. 11Service de Génétique Médicale, Unité d'Oncogénétique, CHU de Montpellier, Montpellier, France
  12. 12Département d'Hématologie, Oncogénétique et Immunologie, CHU de Grenoble site Nord—Institut de biologie et de pathologie, Boulevard de la Chantourne, La Tronche, France
  13. 13Service d'Urologie, Hôpital Européen Georges-Pompidou, AP-HP,  Paris, France
  14. 14Université Paris-Descartes, 12 Rue de l’École de Médecine, Paris, France
  15. 15Département de Médecine Oncologique, Consultation des tumeurs rénales, et INSERM U753, Villejuif, France
  16. 16Génétique Moléculaire et Clinique, Hôpital Edouard Herriot, Lyon, France
  17. 17Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
  18. 18Département de Biopathologie, Service de Génétique, Gustave Roussy Cancer Campus, Villejuif, France
  19. 19Service d'Anatomie et de Cytologie Pathologiques, CHU de Poitiers, Poitiers, France
  20. 20NCCS-VARI Translational Research Laboratory, Division of Medical Sciences, National Cancer Centre, Singapore, Singapore
  21. 21Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore
  22. 22Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, Singapore, Singapore
  23. 23Service d'Anatomie Pathologique, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France
  1. Correspondence to Dr Sophie Gad, Laboratoire de Génétique Oncologique EPHE, INSERM U753, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif 94800, France; sophie.gad{at}gustaveroussy.fr

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.

  • Cancer: urological
  • Molecular genetics
  • predisposing genes
  • PBRM1

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