ingest cdrApp 2018-08-23T20:00:55.277Z d39a25df-af15-48e9-aec2-c9af81a997a2 modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T20:01:46.180Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-08-23T20:01:57.315Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-08-23T20:02:19.908Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T20:02:41.909Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-25T20:19:44.881Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-26T17:44:02.404Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-02-28T01:44:28.520Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-19T21:02:23.187Z Jordan Kardos Author Curriculum in Genetics and Molecular Biology School of Medicine Investigating immune modulation of molecular subtypes of bladder cancer in response to chemotherapy Urinary bladder cancer is the ninth most common malignancy, with ~77,000 new cases and ~16,000 deaths in the United States annually. Muscle-invasive bladder cancer has been described as a heterogeneous disease and several groups have identified intrinsic molecular subtypes. Here, we characterize the claudin-low, molecular subtype of high-grade bladder cancer. Claudin-low bladder tumors are defined by high levels of epithelial-to-mesenchymal transition (EMT), enrichment for tumor initiating cell (TIC) signatures, and low expression levels of tight-junction claudins. Furthermore, we find that claudin-low tumors are highly enriched across all immune gene signatures examined, but also express high levels of immune checkpoint molecules. In contrast to melanoma and non–small-cell lung cancer, the predicted neoantigen burden does not correlate with immune infiltration in bladder cancer. Standard of care for muscle invasive bladder cancer is combination, platinum-based chemotherapy; however treatment with immune checkpoint inhibitors has also been shown to be effective in both platinum refractory as well as platinum ineligible patients. We describe the comprehensive genomic characterization of urachal adenocarcinoma and the first report of global RNA expression profiling of urachal tumors. We find that urachal tumors molecularly resemble colorectal cancer at the level of gene expression and validate previous reports that have shown that urachal tumors harbor genomic alterations in KRAS, APC, and SMAD2/SMAD4 found in colorectal cancer. Our transcriptome studies reinforce the notion from genomic studies that urachal adenocarcinomas resemble colorectal cancer. We further report that these rare tumors have mutations in DNA Mismatch Repair (MMR) proteins and POLE and describe the successful treatment of a patient with the anti–PD-L1 antibody atezolizumab. Our studies and case report highlight the potential utility of precision oncology in rare tumor types that have no clear standard of care therapy. Finally, we describe the effects of cisplatin-based chemotherapy on the tumor microenvironment. We find that Gemcitabine and Cisplatin (GemCis) and Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC) treatment, the two main frontline chemotherapeutic regimens approved for muscle invasive bladder cancer, have differing effects on the tumor microenvironment and that the luminal and basal molecular subtypes have different responses to therapy. MVAC treatment in luminal tumors in particular induces significantly higher levels of immune infiltration and corresponding immune suppression than GemCis treatment. We further show that this effect appears to be induced by a misregulation of the cytokine expression and induction of EMT, and that methotrexate treatment alone, through its inhibition of dihydrofolate reductase, is sufficient to induce a mesenchymal and immune-infiltrated phenotype. In aggregate this work has important implications for how MVAC and GemCis are combined with immune checkpoint blockade. Summer 2018 2018 Genetics Oncology Bioinformatics bladder, cancer, chemotherapy, immune, microenvironment, subtype eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology William Kim Thesis advisor Ian Davis Thesis advisor Joel Parker Thesis advisor Cyrus Vaziri Thesis advisor Albert Baldwin Thesis advisor text Jordan Kardos Creator Curriculum in Genetics and Molecular Biology School of Medicine Investigating immune modulation of molecular subtypes of bladder cancer in response to chemotherapy Urinary bladder cancer is the ninth most common malignancy, with ~77,000 new cases and ~16,000 deaths in the United States annually. Muscle-invasive bladder cancer has been described as a heterogeneous disease and several groups have identified intrinsic molecular subtypes. Here, we characterize the claudin-low, molecular subtype of high-grade bladder cancer. Claudin-low bladder tumors are defined by high levels of epithelial-to-mesenchymal transition (EMT), enrichment for tumor initiating cell (TIC) signatures, and low expression levels of tight-junction claudins. Furthermore, we find that claudin-low tumors are highly enriched across all immune gene signatures examined, but also express high levels of immune checkpoint molecules. In contrast to melanoma and non–small-cell lung cancer, the predicted neoantigen burden does not correlate with immune infiltration in bladder cancer. Standard of care for muscle invasive bladder cancer is combination, platinum-based chemotherapy; however treatment with immune checkpoint inhibitors has also been shown to be effective in both platinum refractory as well as platinum ineligible patients. We describe the comprehensive genomic characterization of urachal adenocarcinoma and the first report of global RNA expression profiling of urachal tumors. We find that urachal tumors molecularly resemble colorectal cancer at the level of gene expression and validate previous reports that have shown that urachal tumors harbor genomic alterations in KRAS, APC, and SMAD2/SMAD4 found in colorectal cancer. Our transcriptome studies reinforce the notion from genomic studies that urachal adenocarcinomas resemble colorectal cancer. We further report that these rare tumors have mutations in DNA Mismatch Repair (MMR) proteins and POLE and describe the successful treatment of a patient with the anti–PD-L1 antibody atezolizumab. Our studies and case report highlight the potential utility of precision oncology in rare tumor types that have no clear standard of care therapy. Finally, we describe the effects of cisplatin-based chemotherapy on the tumor microenvironment. We find that Gemcitabine and Cisplatin (GemCis) and Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC) treatment, the two main frontline chemotherapeutic regimens approved for muscle invasive bladder cancer, have differing effects on the tumor microenvironment and that the luminal and basal molecular subtypes have different responses to therapy. MVAC treatment in luminal tumors in particular induces significantly higher levels of immune infiltration and corresponding immune suppression than GemCis treatment. We further show that this effect appears to be induced by a misregulation of the cytokine expression and induction of EMT, and that methotrexate treatment alone, through its inhibition of dihydrofolate reductase, is sufficient to induce a mesenchymal and immune-infiltrated phenotype. In aggregate this work has important implications for how MVAC and GemCis are combined with immune checkpoint blockade. Genetics Oncology Bioinformatics bladder; cancer; chemotherapy; immune; microenvironment; subtype Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology William Kim Thesis advisor Ian Davis Thesis advisor Joel Parker Thesis advisor Cyrus Vaziri Thesis advisor Albert Baldwin Thesis advisor 2018 2018-08 eng text Jordan Kardos Creator Curriculum in Genetics and Molecular Biology School of Medicine Investigating immune modulation of molecular subtypes of bladder cancer in response to chemotherapy Urinary bladder cancer is the ninth most common malignancy, with ~77,000 new cases and ~16,000 deaths in the United States annually. Muscle-invasive bladder cancer has been described as a heterogeneous disease and several groups have identified intrinsic molecular subtypes. Here, we characterize the claudin-low, molecular subtype of high-grade bladder cancer. Claudin-low bladder tumors are defined by high levels of epithelial-to-mesenchymal transition (EMT), enrichment for tumor initiating cell (TIC) signatures, and low expression levels of tight-junction claudins. Furthermore, we find that claudin-low tumors are highly enriched across all immune gene signatures examined, but also express high levels of immune checkpoint molecules. In contrast to melanoma and non–small-cell lung cancer, the predicted neoantigen burden does not correlate with immune infiltration in bladder cancer. Standard of care for muscle invasive bladder cancer is combination, platinum-based chemotherapy; however treatment with immune checkpoint inhibitors has also been shown to be effective in both platinum refractory as well as platinum ineligible patients. We describe the comprehensive genomic characterization of urachal adenocarcinoma and the first report of global RNA expression profiling of urachal tumors. We find that urachal tumors molecularly resemble colorectal cancer at the level of gene expression and validate previous reports that have shown that urachal tumors harbor genomic alterations in KRAS, APC, and SMAD2/SMAD4 found in colorectal cancer. Our transcriptome studies reinforce the notion from genomic studies that urachal adenocarcinomas resemble colorectal cancer. We further report that these rare tumors have mutations in DNA Mismatch Repair (MMR) proteins and POLE and describe the successful treatment of a patient with the anti–PD-L1 antibody atezolizumab. Our studies and case report highlight the potential utility of precision oncology in rare tumor types that have no clear standard of care therapy. Finally, we describe the effects of cisplatin-based chemotherapy on the tumor microenvironment. We find that Gemcitabine and Cisplatin (GemCis) and Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC) treatment, the two main frontline chemotherapeutic regimens approved for muscle invasive bladder cancer, have differing effects on the tumor microenvironment and that the luminal and basal molecular subtypes have different responses to therapy. MVAC treatment in luminal tumors in particular induces significantly higher levels of immune infiltration and corresponding immune suppression than GemCis treatment. We further show that this effect appears to be induced by a misregulation of the cytokine expression and induction of EMT, and that methotrexate treatment alone, through its inhibition of dihydrofolate reductase, is sufficient to induce a mesenchymal and immune-infiltrated phenotype. In aggregate this work has important implications for how MVAC and GemCis are combined with immune checkpoint blockade. Genetics Oncology Bioinformatics bladder; cancer; chemotherapy; immune; microenvironment; subtype Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology William Kim Thesis advisor Ian Davis Thesis advisor Joel Parker Thesis advisor Cyrus Vaziri Thesis advisor Albert Baldwin Thesis advisor 2018 2018-08 eng text Jordan Kardos Creator Curriculum in Genetics and Molecular Biology School of Medicine Urinary bladder cancer is the ninth most common malignancy, with ~77,000 new cases and ~16,000 deaths in the United States annually. Muscle-invasive bladder cancer has been described as a heterogeneous disease and several groups have identified intrinsic molecular subtypes. Here, we characterize the claudin-low, molecular subtype of high-grade bladder cancer. Claudin-low bladder tumors are defined by high levels of epithelial-to-mesenchymal transition (EMT), enrichment for tumor initiating cell (TIC) signatures, and low expression levels of tight-junction claudins. Furthermore, we find that claudin-low tumors are highly enriched across all immune gene signatures examined, but also express high levels of immune checkpoint molecules. In contrast to melanoma and non–small-cell lung cancer, the predicted neoantigen burden does not correlate with immune infiltration in bladder cancer. Standard of care for muscle invasive bladder cancer is combination, platinum-based chemotherapy; however treatment with immune checkpoint inhibitors has also been shown to be effective in both platinum refractory as well as platinum ineligible patients. We describe the comprehensive genomic characterization of urachal adenocarcinoma and the first report of global RNA expression profiling of urachal tumors. We find that urachal tumors molecularly resemble colorectal cancer at the level of gene expression and validate previous reports that have shown that urachal tumors harbor genomic alterations in KRAS, APC, and SMAD2/SMAD4 found in colorectal cancer. Our transcriptome studies reinforce the notion from genomic studies that urachal adenocarcinomas resemble colorectal cancer. We further report that these rare tumors have mutations in DNA Mismatch Repair (MMR) proteins and POLE and describe the successful treatment of a patient with the anti–PD-L1 antibody atezolizumab. Our studies and case report highlight the potential utility of precision oncology in rare tumor types that have no clear standard of care therapy. Finally, we describe the effects of cisplatin-based chemotherapy on the tumor microenvironment. We find that Gemcitabine and Cisplatin (GemCis) and Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC) treatment, the two main frontline chemotherapeutic regimens approved for muscle invasive bladder cancer, have differing effects on the tumor microenvironment and that the luminal and basal molecular subtypes have different responses to therapy. MVAC treatment in luminal tumors in particular induces significantly higher levels of immune infiltration and corresponding immune suppression than GemCis treatment. We further show that this effect appears to be induced by a misregulation of the cytokine expression and induction of EMT, and that methotrexate treatment alone, through its inhibition of dihydrofolate reductase, is sufficient to induce a mesenchymal and immune-infiltrated phenotype. In aggregate this work has important implications for how MVAC and GemCis are combined with immune checkpoint blockade. Genetics Oncology Bioinformatics bladder; cancer; chemotherapy; immune; microenvironment; subtype Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology William Kim Thesis advisor Ian Davis Thesis advisor Joel Parker Thesis advisor Cyrus Vaziri Thesis advisor Albert Baldwin Thesis advisor 2018 2018-08 eng text Jordan Kardos Creator Curriculum in Genetics and Molecular Biology School of Medicine Urinary bladder cancer is the ninth most common malignancy, with ~77,000 new cases and ~16,000 deaths in the United States annually. Muscle-invasive bladder cancer has been described as a heterogeneous disease and several groups have identified intrinsic molecular subtypes. Here, we characterize the claudin-low, molecular subtype of high-grade bladder cancer. Claudin-low bladder tumors are defined by high levels of epithelial-to-mesenchymal transition (EMT), enrichment for tumor initiating cell (TIC) signatures, and low expression levels of tight-junction claudins. Furthermore, we find that claudin-low tumors are highly enriched across all immune gene signatures examined, but also express high levels of immune checkpoint molecules. In contrast to melanoma and non–small-cell lung cancer, the predicted neoantigen burden does not correlate with immune infiltration in bladder cancer. Standard of care for muscle invasive bladder cancer is combination, platinum-based chemotherapy; however treatment with immune checkpoint inhibitors has also been shown to be effective in both platinum refractory as well as platinum ineligible patients. We describe the comprehensive genomic characterization of urachal adenocarcinoma and the first report of global RNA expression profiling of urachal tumors. We find that urachal tumors molecularly resemble colorectal cancer at the level of gene expression and validate previous reports that have shown that urachal tumors harbor genomic alterations in KRAS, APC, and SMAD2/SMAD4 found in colorectal cancer. Our transcriptome studies reinforce the notion from genomic studies that urachal adenocarcinomas resemble colorectal cancer. We further report that these rare tumors have mutations in DNA Mismatch Repair (MMR) proteins and POLE and describe the successful treatment of a patient with the anti–PD-L1 antibody atezolizumab. Our studies and case report highlight the potential utility of precision oncology in rare tumor types that have no clear standard of care therapy. Finally, we describe the effects of cisplatin-based chemotherapy on the tumor microenvironment. We find that Gemcitabine and Cisplatin (GemCis) and Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC) treatment, the two main frontline chemotherapeutic regimens approved for muscle invasive bladder cancer, have differing effects on the tumor microenvironment and that the luminal and basal molecular subtypes have different responses to therapy. MVAC treatment in luminal tumors in particular induces significantly higher levels of immune infiltration and corresponding immune suppression than GemCis treatment. We further show that this effect appears to be induced by a misregulation of the cytokine expression and induction of EMT, and that methotrexate treatment alone, through its inhibition of dihydrofolate reductase, is sufficient to induce a mesenchymal and immune-infiltrated phenotype. In aggregate this work has important implications for how MVAC and GemCis are combined with immune checkpoint blockade. Genetics Oncology Bioinformatics bladder; cancer; chemotherapy; immune; microenvironment; subtype Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution William Kim Thesis advisor Ian Davis Thesis advisor Joel Parker Thesis advisor Cyrus Vaziri Thesis advisor Albert Baldwin Thesis advisor 2018 2018-08 eng text Kardos_unc_0153D_18043.pdf uuid:8f4618af-6eea-44c0-bc5f-0883f37a75cf 2020-08-23T00:00:00 2018-07-16T18:18:48Z proquest application/pdf 6668456