bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3313: Epigenetic biomarkers of prognosis in stage IIA colon cancer
Authors: Pagotto Sara , Porcellini Elisa , Bacalini Maria G. , Sarti Diletta , Garajova Ingrid , Broseghini Elisabetta , Laprovitera Noemi , Vasuri Francesco , Garagnani Paolo , Mariani-Costantini Renato , Basso Michele , Visone Rosa , Larocca Luigi M. , Ferracin Manuela , Veronese Angelo 
Published: August 2018

Abstract
Adjuvant therapy is a systemic treatment administered after primary tumor resection to reduce the risk of relapse and death in colorectal cancer (CRC) patients. Generally, adjuvant treatment is recommended for stage III and ‘high-risk' stage II CRC (NCCN guidelines). Nonetheless, adjuvant treatment is still debated for stage IIA (T3N0) patients, whose estimated recurrence rate is 15-20% in the absence of any further therapy after resection of the primary tumor. With the aim to find additional prognostic biomarkers that could improve current patient selection, we analyzed the global methylation profile of a discovery group of 10 relapsing/non-relapsing stage IIA colon cancer samples, without any other known risk factor (low-risk), by Illumina Epic 850K array. We identified a panel of 25 Illumina probes that were able to predict recurrence in chemotherapy-naïve patients. Then, we assessed the methylation of the most predictive Cytosine-Guanine (CpG) dinucleotides in 107 stage IIA colon cancer patients from two different cohorts, by EpiTYPER technology. We validated several CpGs as differentially methylated in relapsing vs. non-relapsing CRCs (p&lt;0.05). For these CpG sites, we analyzed the methylation level also in the matching normal mucosa surrounding the tumor, to identify potential premalignant epigenetic lesions. In addition, we examined the association between the methylation level at specific CpG sites and prognostic clinical characteristics, overall survival and time-to-relapse. We concluded that the analysis of epigenetic alterations in archival colon cancer tissues could increase the panel of risk factors predictive for recurrence, and thus improve the selection of patients who could benefit from adjuvant therapy.
Citation Format: Sara Pagotto, Elisa Porcellini, Maria G. Bacalini, Diletta Sarti, Ingrid Garajova, Elisabetta Broseghini, Noemi Laprovitera, Francesco Vasuri, Paolo Garagnani, Renato Mariani-Costantini, Michele Basso, Rosa Visone, Luigi M. Larocca, Manuela Ferracin, Angelo Veronese. Epigenetic biomarkers of prognosis in stage IIA colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3313.
Abstract 3316: Hypermethylation at the SMPD3 promoter is frequently detected in hepatocellular carcinoma tumor tissue and corresponding plasma circulating DNA, and potentially differs by tumor subtype
Authors: Kwee Sandi Alexander , Peplowska Karolina , Tiirikainen Maarit , Song Min-Ae , Wong Linda L. 
Published: August 2018

Abstract
Background: Circulating plasma DNAs may exhibit altered methylation reflective of aberrant epigenetics in tumor tissues, which may present a clinical opportunity for non-invasive assessment of tumor molecular phenotype. Hypermethylation at the promoter region of SMPD3 (Sphingomyelin phosphodiesterase 3), a tumor suppressor gene, has been identified in several genome-wide DNA methylation studies involving tissue specimens of hepatocellular carcinoma (HCC) (Shen et al., 2012; Song et al., 2013). The purpose of this study was to measure and compare SMPD3 promoter hypermethylation (specifically at cg10426893) in tumors, adjacent liver tissue, and circulating cell-free DNA (cfDNA) to examine its potential as a biomarker of HCC corresponding with tumor molecular subtype.
Methods: Blood and liver tissue specimens were collected following written informed consent from 54 patients undergoing partial liver resection for BCLC stage A HCC. DNA methylation was quantified through pyrosequencing analysis of bisulfite-treated DNAs from corresponding tumor tissue, adjacent liver tissue, plasma, and buffy-coat samples. Results were compared within patients using paired t-test. Transcriptomic molecular sub-classification based on the Hoshida classification system (2009) was performed on a subset of 39 tumors to explore potential associations between SMPD3 promoter hypermethylation and HCC molecular subtype.
Results: Levels of SMPD3 promoter methylation were significantly higher in tumor tissue compared to adjacent liver tissue (37.0% vs. 8.8%, p &lt; 0.0001) as well as when compared to cfDNA samples (32.9% vs. 14.3%, p &lt; 0.0001). SMPD3 promoter methylation levels in cfDNA and tumor tissues were also significantly higher than in corresponding buffy-coat samples (p = 0.0146 and p &lt; 0.0001, respectively). Tumors belonging to the S3 molecular sub-class (n = 22) exhibited significantly higher SMPD3 promoter methylation levels than non-S3 tumors (n = 17) (44.1 % vs. 24.1%, p = 0.0166).
Conclusions: Significant increases in DNA methylation involving the promoter region of SMPD3 in HCC tumor tissues are reflected in cfDNA, supporting potential clinical liquid biopsy applications. Preliminarily, this epigenetic alteration appears to be associated with the S3 (differentiation) molecular subtype of HCC.
Citation Format: Sandi Alexander Kwee, Karolina Peplowska, Maarit Tiirikainen, Min-Ae Song, Linda L. Wong. Hypermethylation at the SMPD3 promoter is frequently detected in hepatocellular carcinoma tumor tissue and corresponding plasma circulating DNA, and potentially differs by tumor subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3316.
Abstract 3320: Discovery and development of DNA methylation biomarkers in human papillomavirus related oropharyngeal squamous cell carcinoma
Authors: Ren Shuling , Gaykalova Daria A. , Guo Theresa W. , Favorov Alexander V. , Fertig Elana J. , Khan Zubair , DeJong Peter M. , Ando Mizuo , Liu Chao , Sakai Akihiro , Fukusumi Takahito , Haft Sunny , Sadat Sayed , Gutkind J Silvio , Koch Wayne M. , Califano Joseph A. 
Published: August 2018

Abstract
Purpose: Human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OPSCC) has an improved prognosis compared to cancers associated with tobacco and alcohol exposure, and also exhibits a different composition of epigenetic alterations. In this methylome-wide association study, we identified DNA methylation-based biomarkers with potential utility in screening for HPV positive OPSCC. Experimental Design: In the discovery stage, genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV positive OPSCC tissues and 25 normal tissues. We defined 51 differentially methylated regions (DMRs) with maximal methylation specificity to cancer samples. We used TCGA methylation array data to evaluate the performance of the proposed candidates. Top 20 candidates were validated using quantitative methylation specific PCR (QMSP) in independent 24 HPV related OPSCCs and 22 controls. Results: Supervised hierarchical clustering of 51 DMRs based on TCGA methylation data found that HPV positive OPSCC had significantly higher DNA methylation levels compared to normal samples and head and neck squamous cell carcinoma (HNSCC) without HPV or with different tumor sites. The methylation levels of all top 20 candidates in HPV positive OPSCC were significantly higher than those in normal samples in TCGA data. 16 of these 20 candidates were found by QMSP to have significant higher methylation levels compared with controls. 2 candidates (CCDC181 and OR6S1) had a sensitivity of 100%, while 10 candidates (KCNA3, ITGA4, BEND4, ELMO1, SFMBT2, HOXB4, ZNF439, ZNF93, VSTM2B and ZNF773) had a specificity of 100%. Our 20 candidates were found by the receiver operating characteristic analysis to have a prediction accuracy ranging from 56.3% to 99.8%. Conclusions: This study discovered 20 epigenetic markers for detection of HPV related OPSCC, which can potentially be applied to develop a population based screening test and improve disease management.
Citation Format: Shuling Ren, Daria A. Gaykalova, Theresa W. Guo, Alexander V. Favorov, Elana J. Fertig, Zubair Khan, Peter M. DeJong, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Sunny Haft, Sayed Sadat, J Silvio Gutkind, Wayne M. Koch, Joseph A. Califano. Discovery and development of DNA methylation biomarkers in human papillomavirus related oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3320.
Abstract 3323: Role of RNA methyltransferase METTL3 in melanoma
Authors: Dahal Ujwal , Le Kang , Gupta Mamta 
Published: August 2018

Abstract
Melanoma is the sixth most common cancer in the USA. Introduction of BRAF inhibitors and advances in cancer immunotherapy has greatly improved treatment of melanoma, however, the problem of tumour relapse and therapy resistance persists. Better understanding of the mechanism of development of the diseases is urgently needed to improve therapeutic intervention. Role of DNA and histone modifications have been well established in several diseases, however, RNA modifications, specifically, N6 methyl adenosine (m6A), has only recently begun to be shown to play critical role in cancer. m6A plays crucial roles in mRNA stability, splicing, export, translation and decay and is regulated by: methyltransferase complex proteins METTL3, METTL14, and WTAP; the demethylases FTO and ALKBH5, and the m6A reader proteins. In the present study, we uncover the role of RNA methyltransferase METTL3 in human melanoma cells. METTL3 expression was assessed in 8 melanoma cell lines (A375, A375MA2, A2058, WM164, 451Lu, WM793, SKMEL2, WM3918). Western blotting data revealed METTL3 to be upregulated in seven melanoma cell lines (except A2058) relative to normal melanocytes. To uncover the role of METTL3 in melanoma, we knockdown METTL3 with lentiviral shRNA and studied the effect on melanoma cells tumorigenesis. The colony formation assay revealed reduced colony number in the METTL3 knockdown A375, A375MA2 and WM793 cells relative to the scrambled control cells. The main cause of melanoma associated fatality is its metastatic dissemination we therefore, next sought to investigate whether METTL3 could affect melanoma cells migration and invasiveness. We performed migration and invasion assays to detect the migratory potential of control or METTL3 knockdown A375, A375MA2 and WM793 cells. Interestingly, both migration and invasion was found to be reduced in METTL3 knockdown cells in all the three cell lines examined. RNA dot blot assay demonstrated a decreased m6A level in total RNA of the METTL3 knockdown cells relative to control cells. p16 and p53 mRNA were found to be enriched in m6A immunoprecipitated samples as compared to IgG control, pointing towards a potential role of m6A in regulating expression of melanoma associated genes. Ongoing effort is aimed at identifying what known or novel regulators of the migratory/invasive cascade is regulated by METTL3 and whether it is through m6A mediated or independent mechanisms. In summary, we have shown that METTL3 is overexpressed in human melanoma and play an important role in metastasis.
Citation Format: Ujwal Dahal, Kang Le, Mamta Gupta. Role of RNA methyltransferase METTL3 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3323.
Abstract 3346: PRMT5-mediated methylation of YBX1 regulates NF-kB activity in colorectal cancer
Authors: Hartley Antja-Voy , Wang Benlian , Miyagi Masaru , Mundade Rasika , Hamilton James , Lu Tao 
Published: August 2018

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US with a staggeringly less than 14% survival rate for patients with metastatic disease. This poor clinical outcome for CRC patients is largely attributed to the lack of understanding of the factors that drive CRC progression, leading to a dearth of available treatment strategies for this disease. Today, treatment modalities and clinical management of colorectal cancer (CRC) are fundamentally based on the success of controlling specific tumorigenic pathways. Interestingly, aberrant activation of the transcription factor nuclear factor ĸB (NF-ĸB) is increasingly recognized as a crucial player in CRC progression. Therefore, understanding the mechanisms underlying regulation of NF-ĸB holds great promise for devising new therapeutic strategies for CRC. Recently, we identified the oncogenic protein, Y-box binding protein 1 (YBX1), as a novel activator of NF-κB. Since YBX1 overexpression has also been linked to poor patient outcome in CRC, we sought to further understand whether this YBX1/NF-ĸB axis could be a potential target for CRC treatment. In this study, we discovered that YBX1 is methylated on arginine 205 (YBX1-R205me2), an event that is critical for YBX1-mediated NF-ĸB activation and target gene expression. Additionally, co-immunoprecipitation studies revealed that the R205 to alanine (A) mutant (YBX1-R205A) also significantly diminished the interaction between YBX1 and the p65 subunit of the transcriptionally active NF-ĸB, demonstrating a novel mechanism by which methylation of YBX1 mediates protein-protein interactions. Overexpression of YBX1-R205A significantly attenuated the migration, proliferation, and anchorage-independent growth of a panel of CRC cells, suggesting that YBX1-R205me2 is essential to the oncogenic functions exerted by the YBX1/NF-ĸB axis in CRC. Furthermore, we revealed that protein arginine methyltransferase 5 (PRMT5) is responsible for the methylation of YBX1-R205. Collectively, our novel findings present a complex picture of the sophisticated regulation of NF-ĸB through PRMT5-mediated YBX1-R205 methylation and suggest that pharmacological disruption of the YBX1/NF-κB axis using PRMT5 inhibitors could serve as the basis for new therapeutics that impede YBX1/NF-κB-driven CRC progression.
Citation Format: Antja-Voy Hartley, Benlian Wang, Masaru Miyagi, Rasika Mundade, James Hamilton, Tao Lu. PRMT5-mediated methylation of YBX1 regulates NF-kB activity in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3346.
Abstract 3353: ZNF414 as a functionally relevant transcription factor in pancreatic and breast cancer cells
Authors: Martínez Alejandra Rodríguez , Vuorinen Elisa M. , Shcherban Anastasia , Rajala Nina K. , Nykter Matti , Kallioniemi Anne 
Published: August 2018

Abstract
Background: The Zinc Finger Protein 414 (ZNF414) is a member of the krüppel C2H2-type zinc-finger protein family. ZNF414 is a cargo protein for Karyopherin α7 (KPNA7), a nuclear importer expressed during embryogenesis, absent in most adult tissues but re-expressed in cancer cells. KPNA7 is involved in promoting proliferation and maintaining nuclear morphology in several breast and pancreatic cancer cell lines. Similar effects on cell growth have been evidenced for ZNF414 using in vitro knock-down experiments. Other than this, the function of ZNF414 remains uncharacterized but, as a zinc finger protein with nuclear localization, it is likely to act as a transcription factor. This study aimed at identifying target genes and DNA binding motifs of ZNF414 in pancreatic and breast cancer cells. Methods: We used next generation sequencing methods on Hs700T and MCF-7 cell lines. RNA-seq was used to identify genes regulated by ZNF414 and ChIP-exo and ATAC-seq analyses to uncover its genomic binding regions. Samples for RNA-seq were collected 12h and 24h after transfection with siRNAs targeting ZNF414. For ChIP-exo and ATAC-seq experiments, cells were transfected to transiently overexpress V5-tagged ZNF414. Results: RNA-seq data analyses revealed 33 and 296 differentially expressed genes (DEGs) in Hs700T cells at 12h and 24h time points, respectively. The corresponding amounts of DEGs in MCF-7 cell line were 177 and 556. There were 23 and 108 DEGs in common to both cell lines at 12h and 24h, respectively. Interestingly, gene ontology analyses revealed enrichment of many functional categories related to cellular proliferation in both cell lines, providing a molecular explanation for the observed ZNF414-elicited phenotype. ChIP-exo data was processed using MACE tool and then combined with the ATAC-seq open chromatin signal to identify the most reliable peaks. We looked at the genomic location of these peaks and observed clear enrichment in the promoter and 5'UTR regions, indicating that ZNF414 is a classical transcription factor. Using MEME for de novo motif discovery analyses, we identified several putative binding motifs common to both cell lines, some of which were also found in promoters of DEGs. Conclusion: This study uncovered the transcriptional regulation that underlies the role of ZNF414 as inducer of cellular proliferation in pancreatic and breast cancer cells.
Citation Format: Alejandra Rodríguez Martínez, Elisa M. Vuorinen, Anastasia Shcherban, Nina K. Rajala, Matti Nykter, Anne Kallioniemi. ZNF414 as a functionally relevant transcription factor in pancreatic and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3353.
Abstract 3354: Chemically induced degradation of the transcription factor BCL6
Authors: Kerres Nina , Steurer Steffen , Schlager Stefanie , Bader Gerd , Caligiuri Maureen , Dank Christian , Engen John R. , Ettmayer Peter , Gerlach Daniel , Gerstberger Thomas , Han Bingsong , Iacob Roxana E. , Kessler Dirk , Lancia David R. , Moriz Mayer , Mischerikow Nikolai , Rumpel Klaus , Schnitzer Renate , Voss Tilman , Zheng Xiaozhang , Zoephel Andreas , Kraut Norbert , McConnell Darryl , Pearson Mark , Koegl Manfred 
Published: August 2018

Abstract
The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We have used structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also cause rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and antiproliferative effects than compounds that merely inhibited co-repressor interaction. The fact that the magnitude of effects elicited by this class of BCL6 degrading compounds greatly exceeds that of our equipotent non-degrading inhibitors offers exciting opportunities for the development of BCL6-based lymphoma therapeutics. To support further research, the most potent BCL6 degrading inhibitor is made freely available to the research community as an in vitro tool compound. Please see http://www.opnMe.com for further infos.
Citation Format: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Maureen Caligiuri, Christian Dank, John R. Engen, Peter Ettmayer, Daniel Gerlach, Thomas Gerstberger, Bingsong Han, Roxana E. Iacob, Dirk Kessler, David R. Lancia, Mayer Moriz, Nikolai Mischerikow, Klaus Rumpel, Renate Schnitzer, Tilman Voss, Xiaozhang Zheng, Andreas Zoephel, Norbert Kraut, Darryl McConnell, Mark Pearson, Manfred Koegl. Chemically induced degradation of the transcription factor BCL6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3354.
Abstract 3356: The EWS/FLI1 transcriptome is characterized by marked heterogeneity across Ewing sarcoma cell lines
Authors: Kitchen-Goosen Susan M. , Bowman Megan J. , Adams Marie , Berger Penny , Grohar Patrick J. 
Published: August 2018

Abstract
BACKGROUND: Ewing sarcoma (ES) is the second most common pediatric bone cancer. ES cells are dependent on the activity of the EWS/FLI1 transcription factor for cell survival. EWS/FLI1 drives proliferation, dysregulates the cell cycle and establishes a block in differentiation. Despite the known dependence of Ewing sarcoma on EWS/FLI1, the exact identity of all the downstream targets of EWS/FLI1 is not known. While gene signatures have been reported for EWS/FLI1, these fail to capture the marked heterogeneity in the EWS/FLI1 transcriptome or correlate these expression changes with cellular phenotype. METHODS: Next generation RNA sequencing with deep coverage was used to generate a comprehensive analysis of the EWS/FLI1 transcriptome by silencing EWS/FLI1 in 5 different ES cell lines at two different time points. These results were organized into gene expression networks and signaling nodes were identified by weighted correlation network analysis (WGCNA). The networks were validated by a 500-gene signature of EWS/FLI1 targets using a next generation sequencing capture assay and the Illumina platform. The cellular endpoint of EWS/FLI1 silencing was evaluated by caspase 3,7 cleavage to measure apoptosis, BGAL staining to measure senescence and scratch assays to capture migration. RESULTS: Next generation RNA sequencing with siRNA silencing of EWS/FLI1 revealed marked heterogeneity in the EWS/FLI1 transcriptome among cell lines. Targets of EWS/FLI1 that were common across cell lines exhibited small magnitude gene expression changes (log fold &lt;2), while large magnitude gene expression changes were unique to individual cell lines (log fold&gt;2). When the log fold change in expression was restricted to greater than 2, only 13 common repressed targets and 4 common induced targets were identified in all 5 cell lines. In addition, silencing of EWS/FLI1 induced dramatically different phenotypes across cell lines, where p53 wild-type cell lines underwent senescence and the p53 mutant cell lines did not. Most cell lines did not continue to proliferate with EWS/FLI1 silencing with the exception being the widely used A673 cell line. Cellular migration did not change with EWS/FLI1 silencing in many of the cell lines in contrast to A673 cells. CONCLUSIONS: EWS/FLI1 drives different gene expression signatures and different phenotypes in unique cell lines. This diversity needs to be considered as EWS/FLI1 directed therapies are developed.
Citation Format: Susan M. Kitchen-Goosen, Megan J. Bowman, Marie Adams, Penny Berger, Patrick J. Grohar. The EWS/FLI1 transcriptome is characterized by marked heterogeneity across Ewing sarcoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3356.