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Molecular analysis of renal cell carcinoma with unclassfied histology [copy number alterations]

ABSTRACT: Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell RCC (nccRCC) that have no standard therapy. The oncogenic drivers in these tumors are unknown. We performed a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, Single Nucleotide Polymorphism array, fluorescence in-situ hybridization, immunohistochemistry, and cell-based assays. We identified recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), and MTOR (8%). Integrated analysis revealed distinct molecular subsets, including a subset of 26% uRCC characterized by NF2-loss, dysregulated Hippo-YAP pathway and worse survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85970 | GEO | 2016/10/11

SECONDARY ACCESSION(S): PRJNA339860

REPOSITORIES: GEO

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Molecular analysis of renal cell carcinoma with unclassfied histology [gene expression]

Project description:Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell RCC (nccRCC) that have no standard therapy. The oncogenic drivers in these tumors are unknown. We performed a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, Single Nucleotide Polymorphism array, fluorescence in-situ hybridization, immunohistochemistry, and cell-based assays. We identified recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), and MTOR (8%). Integrated analysis revealed distinct molecular subsets, including a subset of 26% uRCC characterized by NF2-loss, dysregulated Hippo-YAP pathway and worse survival.

2016-10-11 | GSE85897 | GEO

SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma

Project description:Immune checkpoint blockade (ICB) demonstrates durable clinical benefit only in a minority of renal cell carcinoma (RCC) patients. Identifying molecular features that determine response and developing approaches to enhance the response remain an urgent clinical need. Here we found that, in multiple RCC cell lines, targeting the ATR-CHK1 axis with pharmacological inhibitors increased cytosolic DNA accumulation, activated the cGAS-IRF3-dependent cytosolic DNA sensing pathway, and resulted in the inflammatory cytokine expression. SETD2 mutated RCC cell lines or tumor samples were associated with preferential ATR-CHK1 activation over ATM-CHK2 activation. SETD2 knockdown promoted the cytosolic DNA sensing pathway and conferred greater sensitivity in response to ATR-CHK1 inhibition. In murine Renca tumors, Setd2 knockdown and ATR inhibitor VE822 synergistically promoted cytosolic DNA sensing pathway, immune cell infiltration, and immune checkpoint protein expression. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or in combination with VE822 than Setd2 proficient tumors. SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients, but not in non-ICB-treated RCC patients. This study provides a mechanism-based guidance to develop more personalized combination therapy regimens for RCC patients with SETD2 mutations.

2023-07-25 | GSE234732 | GEO

Virtual-Karyotyping with SNP microarrays in morphologically challenging renal cell neoplasms

Project description:Genetic lesions characteristic for RCC subtypes can be identified by virtual karyotyping with SNP microarrays. In this study, we examined whether virtual karyotypes could be used to better classify a cohort of morphologically challenging/unclassified RCC.

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Inactivation of Bap1 Cooperates with Losses of Nf2 and Cdkn2a to Drive the Development of Pleural Malignant Mesothelioma in Conditional Mouse Models

Project description:Mutations/deletions of BAP1, CDKN2A, and NF2 are the most frequent genetic lesions in human MM. We introduced various combinations of these deletions in the pleura of conditional knockout (CKO) mice, focusing on the contribution of Bap1 loss.

2019-05-30 | GSE131942 | GEO

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Project description:Mutation analysis of 10 frequently mutated genes in renal cell carcinoma (BAP1, KDM5C, MET, MTOR, PBRM1, PIK3CA, PTEN, SETD2, TP53, VHL) in plasma DNA of RCC patients using a custom QIASeq panel (MonRec Cohort)

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SETD2-mediated loss of a panel of miRNAs determines MAPK/JNK signaling pathway activation and multidrug resistance in renal cell carcinoma

Project description:Finding the downstream miRNAs of SETD2 in the renal cell carcinoma cell line the coordinated expression of SETD2-miRNAs-MAPK/JNK may be predictive of poor prognostic in patients with RCC. Our findings also emphasize the therapeutic potential of MAP4K4 in RCC therapy and support the development of an effective therapeutic strategy to target MAP4K4 by molecularly targeted approaches

2019-07-31 | GSE135105 | GEO

aCGH data for mesothelioma cell lines

Project description:Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPM. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM. Genomic DNA was harvested from untreated malignant pleural mesothelioma (MPM) cell lines and used to generate gain/loss profiles for each line using aCGH.

2011-05-19 | E-GEOD-29383 | biostudies-arrayexpress

Mesothelioma tumor gene expression profiles

Project description:Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPM. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM. Total RNA from 53 pleural mesothelioma tumors was extracted and hybridized to Affymetrix gene expression arrays to compile a set of gene expression profiling data for this disease.

2011-05-19 | E-GEOD-29354 | biostudies-arrayexpress

Mesothelioma tumor aCGH profiles

Project description:Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPM. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM. DNA from 53 malignant pleural mesothelioma tumors was collected and hybridized to aCGH arrays. Data were analyzed to create gain and loss profiles for each tumor. This submission includes gcNormalized-data.

2011-09-25 | E-GEOD-29902 | biostudies-arrayexpress

Dual Inhibition of DNA methylation and PARP Increases Anti-tumor Efficacy in SETD2 Deficient Kidney Cancer

Project description:Purpose: SETD2 deficiency, a driving force of depleted levels of H3K36me3 due to impaired methyltransferase activity, plays an important role in diverse forms of cancer, most notably in aggressive and metastatic clear cell renal cell carcinomas (ccRCC). Developing novel treatment schema targeting SETD2-compromised cancer cells are urgently needed. Methods: Human kidney cancer cell lines with or without SETD2 deficiency were treated with a DNA Hypomethylating Agent (HMA), a poly(ADP-ribose) polymerase inhibitor (PARPi), and both (HMA + PARPi) in combination in both in vitro and in vivo settings. Cell inhibition, Comet, flow cytometry, western blot, and RNA-sequencing (RNA-seq) gene expression assays as well as bioinformatic analyses were performed to explore the underlying mechanism action. Results: By taking advantage of involvement of SETD2 in DNA methylation and DNA repair, we found the combination treatment of an HMA (5-Aza-CdR/DAC) and a PARPi (Talazoparib/BMN-673) generated increased cytotoxicity in in vitro SETD2-deficient RCC cell lines than in SETD2-proficient cell lines. Furthermore, our results also demonstrate synergetic anti-tumor effects in SETD2 deficiency RCC cell lines when treated with DAC and BMN-673 that include apoptotic induction, increased DNA damage, insufficient DNA damage repair, upregulation of immune responses by STING and transposable elements (TEs), as well as increased genomic instability. Finally, the combination treatment for SETD2-deficient RCCs was also validated using in vivo mouse models. Conclusion: SETD2 deficiency creates a vulnerable epigenetic status to generate efficacious anti-tumor effects via the combination treatment of DAC and BMN-673 in human and mouse RCC systems, making it a precise medicine-based approach for SETD2-compromised cancers.

2023-08-29 | GSE223893 | GEO

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