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Novel genetically engineered mouse models for clear cell renal cell carcinoma with somatic mutations in Bap1, Pbrm1 and Setd2

ABSTRACT: Novel genetically engineered mouse models for clear cell renal cell carcinoma with somatic mutations in Bap1, Pbrm1 and Setd2

PROVIDER: PRJNA821504 | ENA |

REPOSITORIES: ENA

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Novel genetically engineered mouse models for clear cell renal cell carcinoma with somatic mutations in Bap1, Pbrm1 and Setd2

Project description:Kidneys from our advanced GEMMs of early stage cancer renal cancers contain low frequent somatic mutations in Bap1, Pbrm1 and Setd2, enhanced immune clearance and activation of the DNA damage response

2022-04-06 | GSE199795 | GEO

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

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

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

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

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

2012-06-10 | GSE25540 | GEO

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

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

Gene expression analysis of kidney primary tubular epithelial cells (PTECs), SETD2-KD PTECs, PBRM1-KD PTECs and ccRCC derived cell lines

Project description:Transcriptional profiling of human WT-PTECs, SETD2-KD PTECs, PBRM1-KD PTECs, and 10 different ccRCC derived cell lines. ccRCC derived cell lines showed distict expression signatures as compared to PTECs, some of them also present in SETD2-KD PTECs, and/or PBRM1-KD PTECs.

2017-11-01 | GSE89214 | GEO

Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.

Project description: Not available

| S-EPMC6355619 | biostudies-literature

Clear Cell Renal Cell Carcinoma Subtypes Identified by BAP1 and PBRM1 Expression.

Project description: Not available

| S-EPMC5221690 | biostudies-literature

ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [microarray]

Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.

2018-08-14 | GSE102656 | GEO

PBRM1 Knockdown in RCC Cell Lines

Project description:PBRM1 was found to be mutated in a high percentage of clear cell RCCs. We performed knockdown of PBRM1 via siRNA and compared with scrambled control in three different RCC cell lines. PBRM1 siRNA and mock treated cell lines were normalized together with 'hypoxic' clear cell renal tumors and normal renal tissue samples from GSE17818.

2011-01-20 | E-GEOD-22316 | biostudies-arrayexpress

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