title: Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis.
abstract: Why different species are predisposed to different tumor spectra is not well understood. In particular, whether the physical location of tumor suppressor genes relative to one another influences tumor predisposition is unknown. Renal cancer presents a unique opportunity to explore this question. Renal cell carcinoma (RCC) of clear-cell type (ccRCC), the most common type, begins with an intragenic mutation in the von Hippel-Lindau (VHL) gene and loss of 3p (where VHL is located). Chromosome 3p harbors several additional tumor suppressor genes, including BRCA1-associated protein-1 (BAP1). In the mouse, Vhl is on a different chromosome than Bap1. Thus, whereas loss of 3p in humans simultaneously deletes one copy of BAP1, loss of heterozygosity in the corresponding Vhl region in the mouse would not affect Bap1. To test the role of BAP1 in ccRCC development, we generated mice deficient for either Vhl or Vhl together with one allele of Bap1 in nephron progenitor cells. Six2-Cre;Vhl(F/F);Bap1(F/+) mice developed ccRCC, but Six2-Cre;Vhl(F/F) mice did not. Kidneys from Six2-Cre;Vhl(F/F);Bap1(F/+) mice resembled kidneys from humans with VHL syndrome, containing multiple lesions spanning from benign cysts to cystic and solid RCC. Although the tumors were small, they showed nuclear atypia and exhibited features of human ccRCC. These results provide an explanation for why VHL heterozygous humans, but not mice, develop ccRCC. They also explain why a mouse model of ccRCC has been lacking. More broadly, our data suggest that differences in tumor predisposition across species may be explained, at least in part, by differences in the location of two-hit tumor suppressor genes across the genome.
authors.affiliation: Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Gu
authors.affiliation: Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wolff
authors.affiliation: Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Karoliina
authors.initials: K
authors.lastname: Stefanius
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Alana
authors.initials: A
authors.lastname: Christie
authors.affiliation: Department of Molecular Oncology, Genentech, South San Francisco, CA 94080.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Dey
authors.affiliation: Biochemistry.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; Pathology, Pediatrics.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; Radiology, and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pedrosa
authors.affiliation: Internal Medicine (Nephrology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Renée M
authors.initials: RM
authors.lastname: McKay
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; Pathology, payal.kapur@utsouthwestern.edu james.brugarolas@utsouthwestern.edu.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; payal.kapur@utsouthwestern.edu james.brugarolas@utsouthwestern.edu.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D019070:Cell Lineage; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D005813:Genes, Synthetic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000235:genetics* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D013045:Species Specificity; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C575444:BAP1 protein, mouse; D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D043222:Ubiquitin Thiolesterase; C494469:VHL protein, mouse
keywords: BAP1; Six2-Cre; VHL; kidney cancer; kidney stem cells