bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4449: TET1 inhibits gastric cancer metastasis by demethylation and re-expression of PTEN
Authors: Liu Bingya , Pei Yao-fei , Li Jian-fang , Su Liping , Tao Ran , Yan Min , Zhu Zhang-gang 
Published: July 2016

Abstract
TET1 is a member of ten eleven translocation enzymes, which can convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), eventually to promote CpG islands demethylation of specific gene.. In this study, we found that TET1 expression and 5-hmC content were low in tumor tissues compared to its adjacent non-tumor tissues of gastric cancer. Cell proliferation, migration and invasion were enhanced when TET1 knocked down in gastric cancer cell in vitro and in vivo, while it was suppressed when TET1 over-expressed. We also found that PTENis one of the target genes of TET1. TET1 directly binds to the promoter region of PTEN, activates its transcription through demethylating its CpG islands. Knockdown of TET1 results in hypermethylation of PTEN promoter and low expression of PTEN. PTEN knockdown activates AKT and FAK pathway, which are suppressed by PTEN. The activation of PTEN downstream AKT and FAK facilitates tumor migration, invasion and accelerates cell growth. In conclution, we found a novel mechanism that TET1 suppresses tumor cell growth, migration and invasion through conversion PTEN promoter CpG island methylation to demehylation and then re-expression PTEN.
Citation Format: Bingya Liu, Yao-fei Pei, Jian-fang Li, Liping Su, Ran Tao, Min Yan, Zhang-gang Zhu. TET1 inhibits gastric cancer metastasis by demethylation and re-expression of PTEN. [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 4449.
Abstract 4458: Discovery of novel epigenetic biomarkers in premalignant/malignant oral cavity lesions by methylation arrays
Authors: Demokan Semra , Comert Sevde , Ozkoklesen Cansu , Ulusan Murat , Ak Gulsum , Alatli Canan , Dalay Nejat 
Published: July 2016

Abstract
Purpose: The incidence of the oral squamous cell carcinoma (OSCC) is around 50% of all head and neck cancer (HNC), the sixth most common type of cancer in the world. Aberrant hyper/hypo-methylation in the promoter region of some known or putative tumor suppressor/protoonco-genes occurs frequently during the development of various cancers including OSCC. Both of genetic and environmental factors play roles in the carcinogenesis of malignant lesions. Etiological factors predisposing to OSCC are smoking, alcohol and tobacco consumption, snuffuse, viral factors, chronic irritation, iron and various vitamin deficiencies, poor oral hygiene and diseases such as syphilis. Despite the advances in cancer diagnosis and treatment, the 5-year survival rate of OSCC patients is poor and because of advanced stage of disease, it has high mortality and morbidity. Another the most important ethiological factor of OSCC is oral premalignant lesions (OPML), since OPML is related with malignant transformation. In our study, we included three different OPML associated with different risks of leading to malignancy: Oral leukoplakia has a high risk of conversion into malignancy, whereas oral lichen planus and oral lichenoid dysplasia are associated with lower risk. We aimed to investigate the epigenetic characterization of OSCC and OPML relative to the epigenetic changes in these groups.
Experimental Design: Tumor and corresponding healthy tissues from 12 and 10 Turkish patients with OPML and OSCC, respectively were collected. The samples were analyzed histopatologically and after DNA extraction and bisulfite modification, methylation patterns of the samples were investigated by using the Illumina Infinium HumanMethylation450 (450K) BeadChip array.
Results: According to our preliminary results obtained from the methylation array experiments, CpG regions in the UOX, ABCC12, FCRLB, ABL2, LGR6 and SLC22A18 genes were found unmethylated while CpGs located in YPEL-3 were highly methylated (p&lt;0.005).
Conclusion: We concluded the UOX, ABCC12, FCRLB, ABL2, LGR6, SLC22A18 and YPEL-3 may be potential biomarker candidate genes playing role in the transformation mechanism of OPML/OSCC. In the further studies, we will compare the methylation patterns between OPML subgroups to discriminate the potential candidates.
*This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK-SBAG-114S497).
Citation Format: Semra Demokan, Sevde Comert, Cansu Ozkoklesen, Murat Ulusan, Gulsum Ak, Canan Alatli, Nejat Dalay. Discovery of novel epigenetic biomarkers in premalignant/malignant oral cavity lesions by methylation arrays. [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 4458.
Abstract 4465: Targeted disruption of HDAC3 induces terminal myogenic differentiation of embryonal rhabdomyosarcoma
Authors: Phelps Michael , Bailey Jenna , Vleeshouwer-Neumann Terra , Chen Eleanor 
Published: July 2016

Abstract
Embryonal rhabdomyosarcoma (ERMS), one of the most common and lethal pediatric sarcomas, is characterized by an arrest in myogenic differentiation. We have previously shown that treatment of ERMS cells with pan histone deacetylase (HDAC) inhibitors promotes myogenic differentiation. However, the underlying mechanism specific to each HDAC in ERMS remains unknown. We have completed a high-efficiency CRISPR/Cas9 gene knockout screen of class I and II HDAC genes, revealing HDAC3 as a major driver of myogenic suppression in ERMS. HDAC3-deficient ERMS cells showed robust terminal myogenic differentiation with the formation of multinucleated myotubes. Expanding on our in vitro studies, we developed a novel tamoxifen-inducible CRISPR gene-targeting system in ERMS xenografts established in immune-compromised mice. Disruption of HDAC3 in vivo significantly suppressed tumor growth by inducing myogenic differentiation of ERMS cells. By combining inducible CRISPR gene targeting with HDAC3 structure-function analysis, we showed that HDAC3 functions in concert with the nuclear receptor co-repressor (NCOR1 and NCOR2) complex to regulate gene transcription. HDAC3/NCOR binding and HDAC3 deacetylase activity are both required for suppressing myogenic differentiation in ERMS. RNA sequencing analysis of differentially expressed genes in HDAC3-deficient ERMS cells highlighted key pathways dysregulated in ERMS. Our results suggest that epigenetic silencing of the myogenic program is a major mechanism required for ERMS tumor growth. Identification of the essential interaction between HDAC3 and the NCOR transcriptional repressor complex as well as downstream genes and pathways provides important insights into the biology of ERMS tumorigenesis. Our findings highlight potential new drug targets specific to the activity of HDAC3 in order to improve treatment of ERMS patients.
Citation Format: Michael Phelps, Jenna Bailey, Terra Vleeshouwer-Neumann, Eleanor Chen. Targeted disruption of HDAC3 induces terminal myogenic differentiation of embryonal rhabdomyosarcoma. [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 4465.
Abstract 4470: ST3GAL1-associated transcriptomic program portends poor prognosis in glioblastoma
Authors: Chong Yuk Kien , Sandanaraj Edwin , Koh Lynnette , Thangaveloo Moogaambikai , Tan Melanie SY , Koh Geraldene , Toh Tan Boon , Lim Grace GY , Holbrook Joanna , Kon Oi Lian , Nadarajah Mahendran , Ng Ivan , Ng Wai Hoe , Tan Nguan Soon , Lim Kah Leong , Tang Carol S. , Ang Beng Ti 
Published: July 2016

Abstract
Cell surface sialylation has been associated with tumor cell invasiveness in several cancers. Patients with grade IV glioblastoma multiforme (GBM) often show a median survival period of fifteen months, even with the current standard-of-care treatment. Among the reasons for this poor prognosis lies in the cellular and molecular heterogeneity of tumor cells. The Cancer Genome Atlas efforts have shown that histologically identical GBM tumors can be divided into four molecular subtypes based on gene expression, with each subtype corresponding to unique genomic aberrations and clinical outcome. These findings highlight the limitation of relying solely on morphological approaches to diagnose and subsequently treat patients. We conducted a lectin screen with the goal of identifying candidates that stained normal and tumor cells differentially. We identified a sialyltransferase, ST3Gal1 as a mediator of the binding pattern of one such lectin, Peanut Agglutinin. We demonstrate that ST3Gal1 promotes tumor cell invasiveness and enriches for self-renewal potential in the mesenchymal tumor subclass of patients, typified by highly aggressive and recurrent profiles. Depletion of ST3Gal1 extends tumor latency and prolongs survival in mice. Importantly, an enrichment of the ST3GAL1 transcriptomic program portends poor prognosis in glioma patients. Moving forward, since there are no mutations or changes in copy number of ST3GAL1, we explored epigenetic regulation as a possible mechanism. By tapping into data from the NIH Roadmap Epigenome, and transcriptomic analysis of our patient tumor-derived cells, we identified a histone clustering signature that correlates with survival outcome and disease progression. We are currently investigating one such histone modifier, lysine (K)-specific demethylase 1A (LSD1) and its role at modifying ST3GAL1 transcription and activity.
Citation Format: Yuk Kien Chong, Edwin Sandanaraj, Lynnette Koh, Moogaambikai Thangaveloo, Melanie SY Tan, Geraldene Koh, Tan Boon Toh, Grace GY Lim, Joanna Holbrook, Oi Lian Kon, Mahendran Nadarajah, Ivan Ng, Wai Hoe Ng, Nguan Soon Tan, Kah Leong Lim, Carol S. Tang, Beng Ti Ang. ST3GAL1-associated transcriptomic program portends poor prognosis in glioblastoma. [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 4470.
Abstract 4484: Differentially methylation between ER negative and ER positive breast cancer identifies master regulators to expose potential epigenetic drivers of aggressive disease
Authors: Worsham Maria J. , Chen Kang Mei , Datta Indrani , Stephen Josena K. , Chitale Dhananjay , Divine George 
Published: July 2016

Abstract
The majority of published studies investigating driver genes have focused primarily on genomic mutations which have led to novel study designs (basket trials) where patients with a rare mutation, regardless of tumor histology, are matched to a drug expected to work through the mutated pathway. This dominant focus on genomic mutations has yet to configure in epigenetics. There has been relatively little advancement in changing the management of women with ER negative BC, mainly due to a dearth of actionable therapeutic targets. Our drill-down approach to identified an ER negative-specific 16 gene methylation signature (AHNAK, ALPL, ANXA2R, CCND1, CIRBP, CPQ, DST, EGFR, ESR1, GPRC5B, HERC5, IL22RA2, MITF, OBSL1, POU3F3, RB1CC1) starting from a discovery approach (Illumina Infinium HumanMethylation450 BeadChip, 40 ER negative vs. 40 ER positive BC) followed by expression verification, significant rankings in biological pathways (Ingenuity Pathway Analysis), and confirmation by targeted sequencing using Illumina MiSeq.
Causal Networks are small hierarchical networks of regulators that control the expression/methylation of dataset targets. They can enhance understanding of the effect of master regulators on disease or function.
The objective of this study was to identify regulatory networks utilizing IPA's Causal Network Analysis (CNA) in order to illuminate possible causes and mechanisms underlying the biological activities of the 16 candidate gene signature differentiating ER negative from ER positive BC. To reflect expected gene expression direction implied by methylation changes for the 16 candidate genes, the inverse of the methylation ratio from ER negative vs. ER positive tissue was used for CNA.
CNA software identified 4 hierarchical networks and their corresponding master regulatory molecules, diethylstilbestrol, MSH2, 15-ketoprotaglandin E2, and transcription regulator SP1. Diethylstilbestrol and SP1 had direct regulatory influence (depth level 1) to the candidate molecules ALPL, CCND1, EGFR, ESR1 and CCND1, CIRBP, EGFR, ESR1, respectively. CNA raised the profile of ALPL, CCND1, CIRBP, EGFR, ESR1 (5/16 candidate genes) for further consideration as potential epigenetic drivers of ER negative BC.
Support: Komen Foundation: KG110218
Citation Format: Maria J. Worsham, Kang Mei Chen, Indrani Datta, Josena K. Stephen, Dhananjay Chitale, George Divine. Differentially methylation between ER negative and ER positive breast cancer identifies master regulators to expose potential epigenetic drivers of aggressive disease. [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 4484.
Abstract 4500: Normal tissue and data resources for cancer research from the GTEx program
Authors: Guan Ping , Rao Abhi , Volpi Simona , Koester Susan , Moore Helen M. ,   GTEx consortium
Published: July 2016

Abstract
The NIH Common Fund's Genotype-Tissue Expression (GTEx) project aims to study gene expression and regulation across multiple human tissues from approximately 1000 healthy normal postmortem donors. GTEx will provide valuable insights into gene regulation and its tissue specificity, to identify correlations between genetic variations and variations in gene expression levels as expression quantitative trait loci (eQTLs), and to help understand inherited susceptibility to disease.
Initiated in 2010, the GTEx program has generated a large volume of data associated with each donor, including clinical and histopathological, as well as genotyping and gene expression data from whole genome sequencing, whole exome sequencing, expression array, and RNAseq data. The program has published research results in multiple scientific journals over the past year.
The following public resources are available from the GTEx program:
1. GTEx Portal: an open access database of GTEx expression data and analysis results: http://www.gtexportal.org
2. Database of Genotypes and Phenotypes (dbGaP): controlled access of comprehensive GTEx clinical data and raw sequencing data: http://www.ncbi.nlm.nih.gov/gap
3. Access to residual GTEx biospecimens for research: http://www.gtexportal.org/home/samplesPage
4. SOPs and best practices from GTEx biospecimen collections: http://biospecimens.cancer.gov/resources/sops/library.asp
5. GTEx histological image viewer: http://biospecimens.cancer.gov/resources/tissue_image_library.asp
6. GTEx donors’ families website: a lay description of the GTEx project tailored to the GTEx donors’ families: http://www.genome.gov/gtex
GTEx data can be used in combination with other data sets such as The Cancer Genome Atlas (TCGA) and genome-wide association studies (GWAS) to further explore the genetic causes and biology of cancer. The eQTL data from multiple tissues will help prioritize candidate genes within GWAS-associated loci; allow evaluation of tissue specificity of associated loci, and pinpoint target tissues for disease studies. Researchers are using GTEx resources to: study cancer heterogeneity by subtracting normal tissue expression; identify mutations in protein-truncating variants which may cause cancer; and explore gene activity from multiple donors across multiple tissue types to better understand the age/gender bias in cancer and other diseases.
Citation Format: Ping Guan, Abhi Rao, Simona Volpi, Susan Koester, Helen M. Moore, GTEx consortium. Normal tissue and data resources for cancer research from the GTEx program. [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 4500.
Abstract 4503: Actionable mutations and mutational burden in renal cell carcinoma
Authors: Mockus Susan M. , Patterson Sara E. , Pettus Jason R. , Tsongalis Gregory J. 
Published: July 2016

Abstract
Clear cell renal cell carcinoma (CCRCC), the most common subtype of renal cell carcinoma, is a heterogeneous cancer with variable outcomes and molecular aberrations. Further elucidation of mutational profiles and actionable mutations may improve patient outcomes in CCRCC. Somatic mutational profiling via next-generation sequencing was conducted on 30 CCRCC whole section FFPE patient samples to determine the mutational burden as compared to other solid tumor types. The sequencing failure rate for these samples was 20% (6/30). A 358-gene panel was also run on an additional 57 non-CCRCC solid tumor FFPE patient samples (81 samples in total). FASTQ files generated from Illumina's CASAVA software were submitted to the JAX Clinical Genome Analytics (CGA) data analysis pipeline to perform automated read quality assessment, alignment, and variant calling. Identified variants were then submitted for clinical curation using the JAX Clinical Knowledgebase (CKB) for actionable mutational analysis and overall mutational burden. Of the CCRCC sample set, 33% had one or more actionable mutations. This was low compared to actionable mutations in colon (16/16, 100% actionable), TNBC (18/20, 90% actionable), squamous lung (8/9, 89% actionable), and pancreatic (8/12, 67% actionable). Furthermore, the CCRCC set had a low overall mutational burden with 22 ± 6.7 nonsynonymous SNV's as compared to colon (29 ± 11), squamous lung (43 ± 17), and TNBC (31.5 ± 12). However, the pancreatic set had even lower SNV's at 12.7 ± 3.4. The number of indels was comparable across the five sets, except for colon, which averaged 6.9 ± 8.3. Significant copy number variations (CNV’s; amplification validated at greater than or equal to 6 copies) also had a wide range with squamous lung at the highest (11 ± 11), followed by TNBC (5.6 ± 5.0), and then colon (2.3 ± 3.0). Both the CCRCC and pancreatic sets had few CNV's at 0.8 ± 1.5 and 0.17 ± 0.40, respectively. Common mutations identified in the CCRCC set included EPHB6 duplications near S166, which were identified in 25% of samples. Gene specific mutations in CCRCC were also identified in VHL (54%) and SETD2 (21%). These three genes, EPHB6, VHL, and SETD2 have been previously implicated in CCRCC pathogenesis. Six variants identified in VHL were C77*, P86R, Q132fs, A149D, R177fs, and L184fs. Due to the low mutational burden and/or actionable mutations in CCRCC, even large NGS panels may not be adequate to profile somatic mutations and whole exome or whole genome may be more conducive for molecular subtyping of renal cell carcinoma.
Citation Format: Susan M. Mockus, Sara E. Patterson, Jason R. Pettus, Gregory J. Tsongalis. Actionable mutations and mutational burden in renal cell carcinoma. [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 4503.
Abstract 4520: The effect of EPZ011989, an enhancer of Zeste homolog 2 inhibitor, in acute myeloid leukemia
Authors: Fobare Sydney , Miller Cecelia , Orwick Shelley J. , Keilhack Heike , Hertlein Erin , Byrd John C. 
Published: July 2016

Abstract
Enhancer of Zeste Homolog 2 (EZH2) is a catalytic core subunit of the Polycomb repressive complex 2, PRC2. EZH2 catalyzes the tri-methylation of lysine 27 on histone H3 (H3K27me3) which often results in the silencing of associated gene promoters. The over-expression of EZH2 is associated with cancer progression and poor prognosis in solid tumors and hematological malignances. EZH2 mutations in lymphoma generally are activating whereas those in myelodysplasia and acute myeloid leukemia are typically loss of function. Additionally, EZH2 mutations are not isolated to a hotspot and therefore discerning phenotype is challenging. The purpose of this study was to determine if the inhibition of EZH2 induces cell differentiation or apoptosis in AML, and to determine the significance of EZH2 mutations in AML patients. As H3K27me3 deposition is catalyzed by EZH2, we hypothesized that analysis of H3K27me3 levels could differentiate an inactivating EZH2 mutation. We analyzed H3K27me3 levels in AML patient samples with wild type (N = 5) and mutant (N = 3) EZH2, and found that overall H3K27me3 is reduced in the mutant patient samples. Furthermore, the sample with the highest variant allele frequency (VAF) of the EZH2 mutation had noticeably lower levels of H3K27me3 compared to those that had a lower VAF. This finding demonstrates that diminished H3K27me3 levels can predict the presence of an inactivating EZH2 mutation in AML cells. We next assessed if the EZH2 tool molecule EPZ011989 produced a similar phenotype in wild-type EZH2 AML cell lines (Kasumi-1, MOLM-13, and MV4-11). EPZ011989 inhibited H3K27me3 in all of the cell lines at a concentration of 0.625 μM after only four days of treatment. At these concentrations and this time point we demonstrated no change in viability among these three cell lines and only minimal proliferation inhibition in MV4-11 and MOLM-13 cells. Longer time points are currently being investigated as EZH2 inhibitors often induce anti-proliferative effects only after longer incubation periods.
Therefore, our results support that inactivation of EZH2 with EZP011989 in AML cell lines induces the same cell-biochemical consequence (i.e. H3K27me3 loss) associated with EZH2 mutations in AML patients. This potentially will allow diverse pharmacologic studies in cell lines relative to gene targets and also synergistic lethality studies utilizing genetic and pharmacologic screening techniques to potentially develop therapeutic agents to treat this subtype of AML.
Citation Format: Sydney Fobare, Cecelia Miller, Shelley J. Orwick, Heike Keilhack, Erin Hertlein, John C. Byrd. The effect of EPZ011989, an enhancer of Zeste homolog 2 inhibitor, in acute myeloid leukemia. [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 4520.