title: A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene.
  
  
  CONCLUSIONS
  BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Clinical Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Farley
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.|Basic Science Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.affiliation: Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic, Cleveland OH 44195, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland OH, 44195, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mester
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Deparment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas USA.|Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Pena-Llopis
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Deparment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas USA.|Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pavia-Jimenez
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Alana
authors.initials: A
authors.lastname: Christie
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
authors.forename: Cathy D
authors.initials: CD
authors.lastname: Vocke
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
authors.forename: James
authors.initials: J
authors.lastname: Peterson
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Middelton
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kinch
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Grishin
authors.affiliation: Translational Surgical Pathology, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Metwalli
authors.affiliation: McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Cancer Therapy and Research Center, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
authors.forename: Patricia L M
authors.initials: PLM
authors.lastname: Dahia
authors.affiliation: Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic, Cleveland OH 44195, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland OH, 44195, USA.|Department of Genetics and Genome Sciences and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Deparment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas USA.|Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D019143:Evolution, Molecular; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase