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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (46), p.16538-16543
• Main Authors: Wang, Shan-Shan, Gu, Yi-Feng, Wolff, Nicholas, Stefanius, Karoliina, Christie, Alana, Dey, Anwesha, Hammer, Robert E., Xie, Xian-Jin, Rakheja, Dinesh, Pedrosa, Ivan, Carroll, Thomas, McKay, Renée M., Kapur, Payal, Brugarolas, James
• Format: Article
• Language: English
• Subjects: Age of Onset; Alleles; Animals; Biological Sciences; Cancer; Carcinoma, Renal Cell - genetics; Cell Lineage; Chromosome Mapping; Cysts; Disease Models, Animal; Female; Genes; Genes, Reporter; Genes, Synthetic; Genes, Tumor Suppressor; Genetic mutation; Genetic Predisposition to Disease; Humans; Kidney cancer; Kidney cells; Kidney Diseases, Cystic - genetics; Kidney Diseases, Cystic - pathology; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - genetics; Kidney Failure, Chronic - pathology; Kidney Neoplasms - genetics; Kidneys; Lesions; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Genetic; Multipotent Stem Cells - metabolism; Multipotent Stem Cells - pathology; Mutation; Phenotype; Precancerous Conditions - genetics; Precancerous Conditions - pathology; Renal cell carcinoma; Rodents; Species Specificity; Tumor suppressor genes; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology; Tumors; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - physiology; Von Hippel-Lindau Tumor Suppressor Protein - antagonists & inhibitors; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1414789111

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. Significance Despite the discovery of the von Hippel–Lindau ( VHL ) gene in 1993, and that inactivating germ-line mutations of VHL cause multiple kidney lesions, including clear-cell renal cell carcinoma (ccRCC), Vhl inactivation in the mouse does not lead to ccRCC and a mouse model has been lacking. We discovered that the BRCA1-associated protein-1 ( BAP1 ) two-hit tumor suppressor gene is mutated in ccRCC, and one BAP1 allele is frequently somatically codeleted with VHL in tumors. In the mouse, Vhl and Bap1 are on different chromosomes. We show that SIX homeobox 2 ( Six2 ) -Cre;Vhl F/F;Bap1 F/⁺ mice develop premalignant lesions and malignant ccRCC resembling VHL syndrome. More broadly, differences in tumor predisposition across species may result from differences in the location