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 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.

Original languageEnglish (US)
Pages (from-to)16538-16543
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number46
DOIs
StatePublished - Nov 18 2014

Fingerprint

Carcinogenesis
Kidney
BRCA1 Protein
Tumor Suppressor Genes
Renal Cell Carcinoma
Neoplasms
Chromosomes
von Hippel-Lindau Disease
Kidney Neoplasms
Loss of Heterozygosity
Nephrons
Cysts
Stem Cells
Alleles
Genome
Mutation
Genes

ASJC Scopus subject areas

  • General

Cite this

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. / 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 J; McKay, Renee M; Kapur, Payal; Brugarolas, James B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 46, 18.11.2014, p. 16538-16543.

Research output: Contribution to journalArticle

@article{72f5f70ea22a4b98adaf06e5347672c2,
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 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.",
author = "Wang, {Shan Shan} and Gu, {Yi Feng} and Nicholas Wolff and Karoliina Stefanius and Alana Christie and Anwesha Dey and Hammer, {Robert E} and Xian-Jin Xie and Dinesh Rakheja and Ivan Pedrosa and Carroll, {Thomas J} and McKay, {Renee M} and Payal Kapur and Brugarolas, {James B}",
year = "2014",
month = "11",
day = "18",
doi = "10.1073/pnas.1414789111",
language = "English (US)",
volume = "111",
pages = "16538--16543",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "46",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84915822435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84915822435&partnerID=8YFLogxK

U2 - 10.1073/pnas.1414789111

DO - 10.1073/pnas.1414789111

M3 - Article

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

SN - 0027-8424

IS - 46

ER -