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Tushar Patel – 1st expert on this subject based on the ideXlab platform

  • BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma
    Molecular Cancer, 2017
    Co-Authors: Mansi Parasramka, Irene K. Yan, Xue Wang, Phuong Nguyen, Akiko Matsuda, Sayantan Maji, Catherine Foye, Yan Asmann, Tushar Patel

    Abstract:

    BackgroundGenetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies.MethodsThe impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity.ResultsSensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or BAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine.ConclusionsNEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.

  • BAP1 dependent expression of long non coding rna neat 1 contributes to sensitivity to gemcitabine in cholangiocarcinoma
    Molecular Cancer, 2017
    Co-Authors: Mansi Parasramka, Xue Wang, Akiko Matsuda, Sayantan Maji, Catherine Foye, Yan Asmann, Phuong L Nguyen, Tushar Patel

    Abstract:

    Genetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies. The impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity. Sensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or BAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine. NEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.

Mansi Parasramka – 2nd expert on this subject based on the ideXlab platform

  • BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma
    Molecular Cancer, 2017
    Co-Authors: Mansi Parasramka, Irene K. Yan, Xue Wang, Phuong Nguyen, Akiko Matsuda, Sayantan Maji, Catherine Foye, Yan Asmann, Tushar Patel

    Abstract:

    BackgroundGenetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies.MethodsThe impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity.ResultsSensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or BAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine.ConclusionsNEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.

  • BAP1 dependent expression of long non coding rna neat 1 contributes to sensitivity to gemcitabine in cholangiocarcinoma
    Molecular Cancer, 2017
    Co-Authors: Mansi Parasramka, Xue Wang, Akiko Matsuda, Sayantan Maji, Catherine Foye, Yan Asmann, Phuong L Nguyen, Tushar Patel

    Abstract:

    Genetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies. The impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity. Sensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or BAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine. NEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.

  • clear cell renal cell carcinoma subtypes identified by BAP1 and pbrm1 expression
    The Journal of Urology, 2016
    Co-Authors: Richard W. Joseph, Mansi Parasramka, Payal Kapur, Daniel J Serie, Thai H Ho, John C. Cheville, Eugene P Frenkel, Alexander S Parker, James Brugarolas

    Abstract:

    Purpose: In clear cell renal cell carcinoma BAP1 and PBRM1 are 2 of the most commonly mutated genes (10% to 15% and 40% to 50%, respectively). We sought to determine the prognostic significance of PBRM1 and BAP1 expression in clear cell renal cell carcinoma.Materials and Methods: We used immunohistochemistry to assess PBRM1 protein expression in 1,479 primary clear cell renal cell carcinoma tumors that were previously stained for BAP1. A centralized pathologist reviewed all cases and categorized tumors as positive or deficient for PBRM1 and BAP1. Kaplan-Meier and Cox regression models were used to evaluate association of PBRM1 and BAP1 expression with the risk of death from renal cell carcinoma and the risk of metastasis after adjustment for age and the Mayo Clinic SSIGN (stage, size, grade and necrosis) score.Results: PBRM1 and BAP1 expression was PBRM1+ BAP1+ in 40.1% of tumors, PBRM1– BAP1+ in 48.6%, PBRM1+ BAP1– in 8.7% and PBRM1– BAP1– in 1.8%. The incidence of PBRM1 and BAP1 loss in the same tumor w…

Sam M Janes – 3rd expert on this subject based on the ideXlab platform

  • s22 BAP1 expression and treatment outcomes in malignant pleural mesothelioma in a prospective uk based clinical trial
    Thorax, 2017
    Co-Authors: Neelam Kumar, K Kolluri, Al D Rifai, Yuki Ishii, Elaine Borg, Mary Falzon, Andrew G Nicholson, Sam M Janes

    Abstract:

    Objectives Genomic studies of malignant pleural mesothelioma (MPM) have identified frequent mutations in the nuclear deubiquitinase BRCA Associated Protein 1 (BAP1). Previous studies have identified 100% correlation between BAP1 nuclear staining and wild type BAP1 status, pointing to immunohistochemistry (IHC) as a reliable technique to detect BAP1 molecular status. The objective of this study is to assess BAP1 expression and infer molecular status using IHC in a cohort from a prospective UK based clinical trial (MSO1). Furthermore, we aim to evaluate the effect of BAP1 status on treatment outcomes. Methods BAP1 expression was evaluated by IHC in 79 biopsies independently by two consultant histopathologists. Cases were considered positive (wild type BAP1) if strong nuclear staining was present and negative (mutant BAP1) if absent. Results Assessment of BAP1 expression was concordant in 77 of 79 cases (97%). BAP1 expression was negative in 66 of these 77 cases (86%). Patient characteristics and the effect of BAP1 expression on treatment outcomes are in Table 1. Conclusions BAP1 expression was negative in 86% of MPM tumours suggesting a high frequency of BAP1 mutations in this UK cohort. No significant differences in clinical characteristics or outcomes were noted between cases with positive or negative BAP1 expression overall. When analysed by treatment subgroup, there was a trend towards a survival benefit in cases with negative BAP1 expression (BAP1 mutants) in the ASC plus vinorelbine arm, but no statistically significant difference in outcomes within any treatment arm. We plan to further validate our findings by correlating BAP1 expression directly with BAP1 molecular status in this cohort using laser capture microdissection and sequencing.

  • BAP1 expression and treatment outcomes in malignant mesothelioma
    European Respiratory Journal, 2017
    Co-Authors: Neelam Kumar, K Kolluri, Elaine Borg, Mary Falzon, Andrew G Nicholson, Elizabeth K Sage, Sam M Janes

    Abstract:

    Objective: Genomic studies of malignant mesothelioma (MM) have identified frequent mutations in BRCA Associated Protein 1 (BAP1), a nuclear deubiquitinase and transcriptional regulator. Immunohistochemistry (IHC) is a reliable technique to determine BAP1 molecular status. Our objective is to assess BAP1 expression and infer molecular status in a cohort from a prospective UK clinical trial (MSO1) and to determine if BAP1 status is predictive of treatment outcomes. Method: BAP1 IHC was evaluated in 79 tumour biopsies by 2 histopathologists. Cases were considered positive (wild type BAP1) if strong nuclear staining was present and negative (mutant BAP1) if absent. Results: BAP1 expression was negative in 66 of these 77 cases (86%).
    Conclusions: BAP1 IHC was negative in 86% of tumours suggesting a high frequency of BAP1 mutations. There was no significant correlation in clinical characteristics or outcomes with BAP1 status. When analysed by treatment subgroup, there was a trend towards a survival benefit in cases with negative BAP1 expression (BAP1 mutants) in the ASC plus vinorelbine arm, but no statistically significant difference in outcomes within any treatment arm.