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Steve Horvath - One of the best experts on this subject based on the ideXlab platform.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:PURPOSE Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, Histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of Histone Modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:Purpose Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. Methods Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome mea...
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global Histone Modification patterns predict risk of prostate cancer recurrence
Nature, 2005Co-Authors: David Seligson, Steve Horvath, Tao Shi, Sheila Tze, Michael Grunstein, Siavash K KurdistaniAbstract:Aberrations in post-translational Modifications of Histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, Modifications of Histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global Histone Modifications. Here we show that changes in global levels of individual Histone Modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the Histone acetylation and dimethylation of five residues in Histones H3 and H4. Grouping of samples with similar patterns of Modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These Histone Modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific Histone Modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.
Howard Cedar - One of the best experts on this subject based on the ideXlab platform.
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linking dna methylation and Histone Modification patterns and paradigms
Nature Reviews Genetics, 2009Co-Authors: Howard Cedar, Yehudit BergmanAbstract:Both DNA methylation and Histone Modification are involved in establishing patterns of gene repression during development. Certain forms of Histone methylation cause local formation of heterochromatin, which is readily reversible, whereas DNA methylation leads to stable long-term repression. It has recently become apparent that DNA methylation and Histone Modification pathways can be dependent on one another, and that this crosstalk can be mediated by biochemical interactions between SET domain Histone methyltransferases and DNA methyltransferases. Relationships between DNA methylation and Histone Modification have implications for understanding normal development as well as somatic cell reprogramming and tumorigenesis.
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dna replication timing of the human beta globin domain is controlled by Histone Modification at the origin
Genes & Development, 2008Co-Authors: Alon Goren, Amalia Tabib, Merav Hecht, Howard CedarAbstract:The human β-globin genes constitute a large chromosomal domain that is developmentally regulated. In nonerythroid cells, these genes replicate late in S phase, while in erythroid cells, replication is early. The replication origin is packaged with acetylated Histones in erythroid cells, yet is associated with deacetylated Histones in nonerythroid cells. Recruitment of Histone acetylases to this origin brings about a transcription-independent shift to early replication in lymphocytes. In contrast, tethering of a Histone deacetylase in erythroblasts causes a shift to late replication. These results suggest that Histone Modification at the origin serves as a binary switch for controlling replication timing.
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dna replication timing of the human β globin domain is controlled by Histone Modification at the origin
Genes & Development, 2008Co-Authors: Alon Goren, Amalia Tabib, Merav Hecht, Howard CedarAbstract:The human beta-globin genes constitute a large chromosomal domain that is developmentally regulated. In nonerythroid cells, these genes replicate late in S phase, while in erythroid cells, replication is early. The replication origin is packaged with acetylated Histones in erythroid cells, yet is associated with deacetylated Histones in nonerythroid cells. Recruitment of Histone acetylases to this origin brings about a transcription-independent shift to early replication in lymphocytes. In contrast, tethering of a Histone deacetylase in erythroblasts causes a shift to late replication. These results suggest that Histone Modification at the origin serves as a binary switch for controlling replication timing.
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DNA replication timing of the human beta-globin domain is controlled by Histone Modification at the origin.
Genes & development, 2008Co-Authors: Alon Goren, Amalia Tabib, Merav Hecht, Howard CedarAbstract:The human beta-globin genes constitute a large chromosomal domain that is developmentally regulated. In nonerythroid cells, these genes replicate late in S phase, while in erythroid cells, replication is early. The replication origin is packaged with acetylated Histones in erythroid cells, yet is associated with deacetylated Histones in nonerythroid cells. Recruitment of Histone acetylases to this origin brings about a transcription-independent shift to early replication in lymphocytes. In contrast, tethering of a Histone deacetylase in erythroblasts causes a shift to late replication. These results suggest that Histone Modification at the origin serves as a binary switch for controlling replication timing.
David Seligson - One of the best experts on this subject based on the ideXlab platform.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:PURPOSE Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, Histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of Histone Modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:Purpose Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. Methods Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome mea...
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global Histone Modification patterns predict risk of prostate cancer recurrence
Nature, 2005Co-Authors: David Seligson, Steve Horvath, Tao Shi, Sheila Tze, Michael Grunstein, Siavash K KurdistaniAbstract:Aberrations in post-translational Modifications of Histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, Modifications of Histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global Histone Modifications. Here we show that changes in global levels of individual Histone Modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the Histone acetylation and dimethylation of five residues in Histones H3 and H4. Grouping of samples with similar patterns of Modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These Histone Modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific Histone Modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.
Sheila Tze - One of the best experts on this subject based on the ideXlab platform.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:PURPOSE Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, Histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of Histone Modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:Purpose Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. Methods Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome mea...
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global Histone Modification patterns predict risk of prostate cancer recurrence
Nature, 2005Co-Authors: David Seligson, Steve Horvath, Tao Shi, Sheila Tze, Michael Grunstein, Siavash K KurdistaniAbstract:Aberrations in post-translational Modifications of Histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, Modifications of Histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global Histone Modifications. Here we show that changes in global levels of individual Histone Modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the Histone acetylation and dimethylation of five residues in Histones H3 and H4. Grouping of samples with similar patterns of Modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These Histone Modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific Histone Modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.
Ananya Manuyakorn - One of the best experts on this subject based on the ideXlab platform.
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:Purpose Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. Methods Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome mea...
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cellular Histone Modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma results from rtog 9704
Journal of Clinical Oncology, 2010Co-Authors: Ananya Manuyakorn, David Seligson, Sheila Tze, Rebecca Paulus, James J Farrell, Nicole A Dawson, Gardenia Cheunglau, Oscar J Hines, Howard A Reber, Steve HorvathAbstract:PURPOSE Differences in cellular levels of Histone Modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three Histone Modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for Histone H3 lysine 4 dimethylation (H3K4me2), Histone H3 lysine 9 dimethylation (H3K9me2), and Histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each Histone Modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, Histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of Histone Modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.