TY - JOUR
T1 - Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis
AU - Wang, Shan Shan
AU - Gu, Yi Feng
AU - Wolff, Nicholas
AU - Stefanius, Karoliina
AU - Christie, Alana
AU - Dey, Anwesha
AU - Hammer, Robert E
AU - Xie, Xian-Jin
AU - Rakheja, Dinesh
AU - Pedrosa, Ivan
AU - Carroll, Thomas J
AU - McKay, Renee M
AU - Kapur, Payal
AU - Brugarolas, James B
PY - 2014/11/18
Y1 - 2014/11/18
N2 - 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 clearcell 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;VhlF/F;Bap1F/+ mice developed ccRCC, but Six2-Cre;VhlF/F mice did not. Kidneys from Six2-Cre;VhlF/F;Bap1F/+ 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.
AB - 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 clearcell 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;VhlF/F;Bap1F/+ mice developed ccRCC, but Six2-Cre;VhlF/F mice did not. Kidneys from Six2-Cre;VhlF/F;Bap1F/+ 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.
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U2 - 10.1073/pnas.1414789111
DO - 10.1073/pnas.1414789111
M3 - Article
C2 - 25359211
AN - SCOPUS:84915822435
SN - 0027-8424
VL - 111
SP - 16538
EP - 16543
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -