Identification of transcriptional changes upon genetic deletion of Vhl, Pbrm1 and double deletion of both Vhl and Pbrm1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE83597 | GEO | 2017/03/06
SECONDARY ACCESSION(S): PRJNA326457
REPOSITORIES: GEO
Similar Datasets
Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The RNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal kidney cortices were labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays.
2012-06-09 | E-GEOD-36895 | biostudies-arrayexpress
Project description:1. PBRM1 loss elicited very similar transcriptional changes as KDM5C loss; 2. PBRM1 loss, and to a lesser extent KDM5C loss, elicited greater transcriptional response in VHL-/- cells than that in VHL+/+ cells.
2018-11-05 | GSE108229 | GEO
Project description:Vhl and Pbrm1 double deletion effect on kidney
| PRJNA326726 | ENA
Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice retained >92% of mutations and exhibited similar DNA copy number alterations to corresponding primary tumors. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The genomic DNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal samples were labeled and hybridized to Affymetrix SNP arrays 6.0.
2012-06-09 | E-GEOD-25540 | biostudies-arrayexpress
Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice retained >92% of mutations and exhibited similar DNA copy number alterations to corresponding primary tumors. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
2012-06-10 | GSE25540 | GEO
Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
2012-06-10 | GSE36895 | GEO
Project description:PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler. The inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. Here we show that in VHL-deficient ccRCC tumors, PBRM1 loss results in an altered PBAF complex that retains the association between SMARCA4 and ARID2 but disengages BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proxy regions to distal enhancer regions. The ATPase function of SMARCA4 enhances the recruitment of nuclear factor RELA to aberrant sites and promotes NF-κB activity. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
2023-02-13 | GSE152734 | GEO
Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.
2022-03-12 | GSE183976 | GEO
Project description:Besides the truncal VHL mutations, ccRCC is characterized by upregulated MTOR signals from both preclinical and clinical studies. To understand how upregulated MTOR signals cooperate with VHL loss in promoting kidney tumorigenesis, we generated kidney-specific deletion of Vhl and Tsc1 (Vhl;Tsc1 cDKO) in mice. The mice showed decreased life span with maximal age of 11 weeks, bilateral polycystic kidney diseases from ~3 weeks and multifocal solid renal cell carcinoma with eosinophilic cytoplasm and grade 2-3 from 7 weeks old. The mouse tumors resemble histology of the human kidney tumors with VHL and TSC1 mutations. To understand the mechanism of how Tsc1 loss cooperates with Vhl loss in promoting tumorigenesis, we performed transcriptomic, metabolomic and immunohistochemical profilings of renal cortices from age-matched wild-type, Vhl or Tsc1 single knockout, and Vhl;Tsc1 cDKO mice. Tsc1 loss cooperates with Vhl loss by augmenting the HIF1 transcriptional output, as well as altering the glutamine/glutamate metabolism, urea cycle, glycogen metabolism, and activating NRF2 signaling pathways which reprogram the cells to counteract the high oxidative stress associated with the proliferation. Our study reports a ccRCC mouse model recapitulating human ccRCC with same genetic background, provides mechanistic insights concerning cooperation between upregulated mTORC1 signals and VHL loss, generates in vivo reagents for studying ccRCC, and implicates potential clinical values.
2022-05-01 | GSE131735 | GEO
Project description:PBRM1 is a component of the PBAF chromatin remodelling complex and has been observed to be deregulated in a significant proportion of patients with clear-cell Renal Cell Carcinoma (ccRCC). This study employs RNA-Seq to identify differentially expressed genes in cellular models of ccRCC by expressing PBRM1 in PBRM1-deficient Caki2 cells.
2016-05-04 | GSE76199 | GEO