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Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16538-43. doi: 10.1073/pnas.1414789111. Epub 2014 Oct 30.

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis.

Author information

1
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;
2
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
3
Department of Molecular Oncology, Genentech, South San Francisco, CA 94080.
4
Biochemistry.
5
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; Pathology, Pediatrics.
6
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.
7
Internal Medicine (Nephrology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
8
Departments of Developmental Biology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
9
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.
10
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.

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.

KEYWORDS:

BAP1; Six2-Cre; VHL; kidney cancer; kidney stem cells

PMID:
25359211
PMCID:
PMC4246264
DOI:
10.1073/pnas.1414789111
[Indexed for MEDLINE]
Free PMC Article

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