bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4460: Precision cancer risk diagnosis by accumulation of epigenetic alterations
Authors: Ushijima Toshikazu , Asada Kiyoshi , Maeda Masahiro , Nakajima Takeshi , Shimazu Taichi 
Published: July 2016

Abstract
Background and Aim: Aberrant DNA methylation is induced by chronic inflammation, and can be accumulated in normal-appearing tissues [reviewed in Ushijima and Hattori, Clin Cancer Res, 2:143, 2012]. Cross-sectional studies have shown that the degree of accumulation of aberrant DNA methylation was correlated with cancer risk, especially inflammation-associated cancers. In this study, we aimed to demonstrate that cancer risk can be predicted by an epigenetic cancer risk marker by a multicenter prospective cohort study.
Methods: We enrolled 826 patients with early gastric cancer, aged 40-80 years, who had undergone endoscopic resection. If a patient had active Helicobacter pylori (H. pylori) infection, the patient was enrolled after eradication of H. pylori. At the time of enrollment, one gastric biopsy was taken, and methylation levels of three preselected genes, miR-124a-3, EMX1 and NKX6-1, were measured by quantitative methylation-specific PCR. The patients were followed up annually by endoscopy to detect metachronous gastric cancer. To exclude cancers undetected at the time of enrollment, “authentic” metachronous gastric cancers were defined as those developed 1 year after enrollment.
Results: With a median follow-up of 2.97 years, 782 of 826 patients had at least one follow-up. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1-2, 2-3 and ≥3 years after the enrollment, respectively. The highest quartile of the miR-124a-3 methylation level had a significantly high HR in univariate analysis (95% CI) [2.17 (1.07 - 4.41); p = 0.032] and adjusted HR in multivariate analysis [2.30 (1.03 - 5.10); p = 0.042] [Asada et al, Gut, 64:388, 2015]. More importantly, with a median follow-up of 4.84 years, a multivariate analysis yielded a larger HR [2.79 (1.34 - 5.81)] with a smaller p value (0.0061).
Conclusions: This study, for the first time, demonstrated the usefulness of an epigenetic cancer risk marker by a multicenter prospective cohort study. DNA methylation accumulated in normal-appearing tissues was considered to be highly useful for precision cancer risk diagnosis.
Citation Format: Toshikazu Ushijima, Kiyoshi Asada, Masahiro Maeda, Takeshi Nakajima, Taichi Shimazu. Precision cancer risk diagnosis by accumulation of epigenetic alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4460.
Abstract 4462: Cytotoxic effects of a novel BRD4 inhibitor in uveal melanoma cells with Gnaq/11 mutations
Authors: Ambrosini Grazia , Schwartz Gary K. 
Published: July 2016

Abstract
Uveal melanoma (UM) is an aggressive intraocular malignancy with high tendency to metastasize to the liver. The majority of UM harbor activating mutations in the G proteins Gnaq/11, and amplification of the oncogene c-Myc. Currently available drugs have shown limited response in patients with UM and there is an urgent need for new effective therapies. Recent findings from our laboratory demonstrated that UM cells with Gnaq/11 mutations are dependent on BRD4 activity. BET proteins are epigenetic readers involved in chromatin remodeling and transcriptional regulation. BRD4 inhibitors consist of small molecules that competitively displace BRD4 from acetylated histones, resulting in the suppression of the MYC transcriptome and other BRD4-dependent genes. Here, we report that a novel clinical BRD4 inhibitor from Plexxikon (Berkeley, CA), PLX51107, induces high cytotoxic activity in UM cell lines at nanomolar concentrations. In cells with Gnaq/11 mutations, PLX51107 showed an IC50 of 250nM, similar to the pre-clinical compound JQ1. In contrast, PLX51107 did not have a significant effect (IC50&gt;3000nM) in cells without the mutations. PLX51107 induced marked apoptosis in Gnaq/11 mutant cells, as detected by Annexin V staining and induction of cleaved PARP. It also suppressed the expression of BRD4 targets, i.e c-Myc, Rad51, and induced the pro-apoptotic protein Bim. In mouse xenograft models of UM PLX51107 significantly inhibited tumor growth. Since the MAPK pathway plays a major role in UM, we explored the combination of PLX51107 with a MEK inhibitor, and found increased activity in vitro and in vivo. All together, these observations support the idea that this clinical BRD4 inhibitor represents a novel therapeutic intervention against UM with Gnaq/11 mutations, and clinical development is planned.
Citation Format: Grazia Ambrosini, Gary K. Schwartz. Cytotoxic effects of a novel BRD4 inhibitor in uveal melanoma cells with Gnaq/11 mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4462.
Abstract 4471: Overcoming the resistance to the anti CD20 treatments in chronic lymphocytic leukaemia
Authors: Scialdone Annarita , Kofoed Damm Jesper , Gullberg Urban , Drott Kristina 
Published: July 2016

Abstract
Chronic lymphocytic leukaemia is the most common leukaemia in the Western countries. Treatment of CLL and other lymphomas is based on cytostatic drugs in combination with rituximab or other monoclonal antibodies targeting the B-cell surface marker CD20. Although the CD20-antibodies have revolutionized the therapeutic perspectives of indolent B-cell lymphomas, the treatment of CLL with CD20-antibodies is often inefficient, a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown previously that CD20 is epigenetically regulated in some lymphoma cell lines and that some histone deacetylase inhibitors (HDACi) can increase CD20 expression in B-cell lymphomas both in vitro and in vivo. Therefore, we utilized the HDACi valproate to upregulate CD20 both in CLL cell lines and in patients.Two CLL patients with del13q were treated with valproate at serum levels around 800 μM for three days in three 21-day cycles. CD20 expression was analyzed by Real time-PCR and flowcytometry on the B-CLL cells isolated from peripheral blood.In addition, the valproate-induced histone modifications and changes in repressor/activator complexes of the CD20 promoter were investigated in the CLL cell lines and in patients.In the patient 1, CD20 expression was increased 2 times after 2 weeks of treatment, suggesting long-term effects by valproate. Neither the mRNA stability nor the protein stability seems to be affected by Valproate, suggesting transcriptional effects. However, no effects were observed in the patient 2. In contrast to patient results, Valproate increases CD20 transcript and protein levels by 2,5 times in the CLL-cell line I83-E95 after 48 hours. Here, the activating histone mark, acetylated H3K9, is enriched on the CD20 promoter suggesting valproate-related effects on the epigenome. Our study will continue the characterization of valproate-related effects on the epigenetic signatures of the CD20 promoter in CLL cells in vitro and in vivo, dissecting the mechanisms underling low CD20 expression in CLL.
Citation Format: Annarita Scialdone, Jesper Kofoed Damm, Urban Gullberg, Kristina Drott. Overcoming the resistance to the anti CD20 treatments in chronic lymphocytic leukaemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4471.
Abstract 4477: Loss of EZH2 accelerates STAT5 loss mediated fatty liver and cancer development through non-methyltransferase function
Authors: Bae Woo Kyun , Shim Hyun Jeong , Cho Sang Hee , Chung Ik-Joo , Kim Kyung Keun 
Published: July 2016

Abstract
Background: The molecular mechanisms underlying the development of fatty liver and hepatocellular carcinoma are not fully understood. Loss of STAT5 from liver tissue results in hepatosteatosis and hepatocellular carcinoma (HCC). Enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human HCC. STAT5 recruits EZH2, which represses a substantial subset of genes regulated by STAT5 during B lymphopoiesis. However, it is not clear if EZH2 can affect STAT5-target genes in liver.
Methods: To investigate the role of STAT5 and EZH2 in liver, mice were generated that carried EZH2fl/fl alleles, STAT5fl/fl alleles, EZH2fl/flSTAT5fl/fl alleles and an Alb-Cre transgene. Lipid analysis in serum and liver, and RNA-seq were examined at 3 & 8 months of age. Mice were also examined by chronic 3 months injection by carbon tetrachloride (CCl4).
Results: The deletion of STAT5 in hepatocyte caused fatty liver and increased cholesterol in serum and liver. The deletion of EZH2 did not make a difference in H3K27me3 expression, and lipid in serum and liver. However, combined loss of EZH2 and STAT5 caused severe fatty liver, increase triglyceride and the ratio liver/body weight compare to STAT5 KO mice (the ratio; 0.097 vs. 0.058, p &lt; 0.05). In response to 3 months treatment with CCl4, combined loss of EZH2 and STAT5 showed accelerated development of hepatocellular carcinoma at 12 months of age. Transcriptome analysis identified the expression of several genes was significantly increased (cd36, pparγ, cyp4a14, lipoprotein lipase, fasn) and decreased (nox4, bbc3, bcl2l1, cdkn2b) which were well known as STAT5 target genes in combined loss of EZH2 and STAT5.
Conclusions: This work demonstrates that loss of EZH2 in liver affects the expression of STAT5 target genes and accelerates STAT5 loss mediated fatty liver and hepatocellular carcinoma development through non-methyltransferase function.
Citation Format: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, Kyung Keun Kim. Loss of EZH2 accelerates STAT5 loss mediated fatty liver and cancer development through non-methyltransferase function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4477.
Abstract 4478: EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma
Authors: Staumont Bernard , Costa Chrisostome , Vandermeers Fabian , Neelature Sriramareddy Sathya , Mascaux Céline , Scherpereel Arnaud , Duysinx Bernard , Louis Renaud , Delvenne Philippe , Hubert Pascale , Willems Luc 
Published: July 2016

Abstract
Background: Malignant pleural mesothelioma (MPM) is a cancer of the pleura mainly caused by exposure to asbestos fibers. Current treatments are unsatisfactory due to intrinsic chemoresistance of the tumor. We hypothesized that chemoresistance was due to epigenetic errors and evaluated the ability of HDAC inhibitors to improve treatment efficacy. We previously showed that valproic acid (VPA) improves the first line regimen of MPM both in vitro and in vivo (Vandermeers et al, 2009, Clinical Cancer Research 15: 2818). A clinical trial also demonstrated that VPA in combination with doxorubicin increases the response rate of second line patients (Scherpereel et al, 2011, European Respiratory Journal 37:129).
Methods: Transcriptomic profiling was performed by microarray analyses (Agilent). Gene expression was validated by quantitative RT-qPCR. Modulation of TGFα expression was performed by shRNA interference and transfection of a cDNA vector. Onset of apoptosis was assessed with the Annexin V assay.
Results: To evaluate the mechanisms associated with the response to chemotherapy, we compared two types of MPM cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Microarray analyses and bioinformatic modeling of gene expression profiles revealed the most relevant candidate genes associated with sensitivity or resistance to this regimen. Among these, TGFα expression was associated with resistance to doxorubicin + VPA in a series of MPM cell lines. Silencing of TGFα by RNA interference in H28 cells correlated with a significant increase in apoptosis. On the other hand, overexpression of TGFα desensitized M14K cells to doxorubicin+VPA -induced apoptosis. Since TGFα interacts with the EGF receptor, we evaluated pharmacological inhibition using EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) and the dual HDAC/EGFR inhibitor CUDC-101. As predicted, these TKI inhibitors improved efficacy of doxorubicin+VPA.
Conclusions: Our data demonstrate that TGFα is involved in resistance of MPM to chemotherapy and that TKI inhibitors overcome resistance to second line regimen.
Citation Format: Bernard Staumont, Chrisostome Costa, Fabian Vandermeers, Sathya Neelature Sriramareddy, Céline Mascaux, Arnaud Scherpereel, Bernard Duysinx, Renaud Louis, Philippe Delvenne, Pascale Hubert, Luc Willems. EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4478.
Abstract 4480: Blood epigenetic age may predict cancer incidence and mortality
Authors: Zheng Yinan , Joyce Brian T. , Colicino Elena , Liu Lei , Zhang Wei , Dai Qi , Shrubsole Martha J. , Kibbe Warren A. , Gao Tao , Zhang Zhou , Jafari Nadereh , Schwartz Joel , Baccarelli Andrea A. , Hou Lifang 
Published: July 2016

Abstract
Biological measures of aging are important for understanding age-related cancers as the population ages. Since the epigenome is closely related to aging, epigenetics may help predict these and other age-related diseases. We aimed to prospectively examine whether blood Δage (the discrepancy between epigenetic and chronological age) can predict cancer incidence/mortality. In a prospective cohort (the Normative Aging Study), Δage and its rate of change over time were calculated using Illumina Human Methylation 450K array data in 834 blood leukocyte samples longitudinally collected from 442 participants free of cancer at the blood draw. About 3-5 years before cancer onset or death, Δage was associated with cancer risks in a dose-responsive manner (test for trend P = 0.02) and time-dependent Cox models showed a one-year increase in Δage was associated with all-cancer incidence (HR (hazard ratio): 1.06, 95% CI: 1.02-1.10) and mortality (HR: 1.17, 95% CI: 1.07-1.28). Participants with smaller Δage and decelerated epigenetic aging over time had the lowest risks of cancer incidence (log-rank P = 0.003) and mortality (log-rank P = 0.02). Spline analysis suggested Δage was associated with cancer incidence in a ‘J-shaped’ manner, and with cancer mortality in a time-varying manner. We conclude that blood epigenetic age may mirror epigenetic abnormalities related to cancer early development or the immune response to it. Those with older epigenetic age relative to their chronological age have an elevated risk of cancer events within 3-5 years. Thus, epigenetic age could potentially serve as a novel, minimally invasive biomarker for cancer prediction.
Citation Format: Yinan Zheng, Brian T. Joyce, Elena Colicino, Lei Liu, Wei Zhang, Qi Dai, Martha J. Shrubsole, Warren A. Kibbe, Tao Gao, Zhou Zhang, Nadereh Jafari, Joel Schwartz, Andrea A. Baccarelli, Lifang Hou. Blood epigenetic age may predict cancer incidence and mortality. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4480.
Abstract 4482: Expression profiling of SETD family genes in breast cancer patients
Authors: Matos Neto Joao N. , do Amaral Rabello Doralina , Pittella-Silva Fabio 
Published: July 2016

Abstract
Epigenetic alterations have recently been recognized to play an important role in the progression of many tumor types. Protein methyltrasferases are among the most relevant epigenetic effectors. Dysregulation in the expression or activity of these enzymes is among the major epigenetic alterations involved in carcinogenesis. Methyltransferases of the SETD family share a SET domain which is involved in the methylation of lysine residues on histones and non-histone proteins. So far, little is known about the relation of SETD family genes with mammary carcinogenesis. In the present study we evaluated the relative expression of 10 SETD family genes in 18 breast tumor samples and non-tumor breast tissues from patients with breast cancer by real time qPCR. The comparative expression profile of each gene was correlated with the most relevant clinicopathologic prognostic information available from patients. We found a significant increase in the expression of SETMAR in tumor samples compared with the normal breast tissues. In addition, triple negative tumor subtype (n = 7), when compared with a pool of normal tissue samples (n = 13) presented an increased relative expression of SETMAR. Interestingly, SETD8 was 10 times overexpressed when the angiolymphatic invasion (n = 8) was present compared to the absence of this feature (n = 10). Patients with strong axillary tumor burden defined as the presence of at least 10 axillary lymph nodes with cancer (n = 6), showed an increased relative expression of SETD5 and SETD8 genes when compared to the absence of this feature (n = 12). Evaluating the expression on paired samples (normal tissue and tumor tissue from the same patient (n = 7), we observed an increased relative expression of SETD1B. Also in the paired samples, we found a strong correlation among the expression of the genes SETD1B, SETD5, SETD8 and SETMAR in tumor samples with no correlation in normal tissues. Furthermore, immunohistochemical analysis revealed a stronger expression of SETD5 and SETMAR in carcinomas in situ when compared to normal tissues and invasive tumors. Taken together, these data points to a likely role of SETMAR and SETD1B genes in mammary carcinogenesis, with relevant clinical implications and with the possible involvement of SETD5 and SETD8 genes in more advanced stages of the disease. The correlation on the expression of these genes with relevant clinical prognostic factors in breast cancer opens the way to exploit them not only as therapeutic targets, but also as new prognostic markers.
Keywords: SETD gene family, expression profile, breast cancer
Citation Format: Joao N. Matos Neto, Doralina do Amaral Rabello, Fabio Pittella-Silva. Expression profiling of SETD family genes in breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4482.
Abstract 4501: Immunophenotypic identities of clinical samples have the potential to correlate with overall survival in cytogenetically normal AML patients
Authors: Gaj Pawel , Nowis Dominika , Volinia Stefano 
Published: July 2016

Abstract
Tumor infiltrating lymphocytes (TILs) have been described to have great potential to modulate course of the disease. Capacity to eliminate cancer cells primarily depends on the interplay between tumor and its microenvironment. Despite the great interest which this topic gathered over last decades the role of immune cells interaction with cancer has hardly been studied in acute myeloid leukemia patients.
Multitude of patient-specific factors, as well as a great repertoire of different kinds of tumor-infiltrating immune cells, potentially affecting disease progression should be the motivation to investigate implication of tumor immune cells interplay in possibly maximized cohorts of patients. Due to technical reasons the traditional microscopy-based techniques do not allow for the desired high-throughput approach.
In the present study we demonstrate an inter-platform-compatible method which allowed us to predict the gene expression component involvement of 37 cell populations representing different stages of hematopoietic linage differentiation. The predictions were done for an extensive set of peripheral blood mononuclear cells (PBMC) and bone marrow aspirate material sampled from cytogenetically normal (CN) AML cases.
Our results nicely confirmed poor survival prognosis observed for the patients demonstrating high contribution of the CD34+, CD38- hematopoietic stem cells in their bone marrow samples HR = 2.05, 95%CI = 1.22-3.43, p-value = 6.73E-03. We also show that a specific Mature NK cell_CD56+ CD16+ CD3- component found in gene expression signatures of bone marrow samples correlated independently with significantly worse survival in CN AML patients HR = 2.56, 95%CI = 1.49-4.42, p-value = 7.03E-04.
Same analysis carried for the CN AML PBMC samples indicated independent positive effects for the predicted involvement of the Erythroid_CD34+ CD71+ GlyA- and Hematopoietic stem cell_CD133+ CD34dim cell populations in The Cancer Genome Atlas (TCGA) CN AML cohort.
Acknowledgements
The research was supported by a grant from European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION, a grant from the Ministry of Science and Higher Education of Poland [IP2012 048172 (DN)], and a grant from the National Science Centre Poland [2013/10/E/NZ5/00778 (DN)].
Citation Format: Pawel Gaj, Dominika Nowis, Stefano Volinia. Immunophenotypic identities of clinical samples have the potential to correlate with overall survival in cytogenetically normal AML patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4501.